Coding variants in human double-strand break DNA repair genes

Coding variants in human double-strand break DNA repair genes

Mutation Research 509 (2002) 175–200 Coding variants in human double-strand break DNA repair genes Cindy C. Ruttan, Barry W. Glickman∗ Centre for Bio...

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Mutation Research 509 (2002) 175–200

Coding variants in human double-strand break DNA repair genes Cindy C. Ruttan, Barry W. Glickman∗ Centre for Biomedical Research and the Department of Biology, University of Victoria, P.O. Box 3020 STN CSC, Victoria, BC, Canada V8W 3N5

Abstract DNA repair is essential for the maintenance of genomic integrity. Consequently, altered repair capacity may impact individual health in such areas as aging and susceptibility to certain diseases. Defects in some DNA repair genes, for example, have been shown to increase cancer risk, accelerate aging and impair neurological functions. Now that over 115 genes directly involved in human DNA repair have been characterized at the DNA sequence level, the identification of single nucleotide polymorphisms (SNPs) in DNA repair genes is becoming a reality. This information will likely lead to the identification of alleles, or combinations of alleles that affect disease predisposition. This communication summarizes SNPs identified to date in the coding region of 24 human double-strand break repair (DSBR) genes. SNP data for four of these genes were obtained by screening at least 100 individuals in our laboratory. For each SNP, the codon number, amino acid substitution, allele frequency and population information is supplied. © 2002 Elsevier Science B.V. All rights reserved. Keywords: DNA repair; Double-strand breaks; Single nucleotide polymorphisms (SNPs); Molecular epidemiology; Human disease; Cancer; Aging

1. Introduction

1.1. Double-strand break repair

DNA is subjected to constant challenge from both endogenous and exogenous damaging agents. Multiple pathways have evolved to remove, repair or bypass DNA lesions and, to date, over 115 human DNA repair genes have been identified [1,2]. Most of these are participants in the four major DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and double-strand break (DSBR).

Double-strand DNA breaks are arguably the most serious form of DNA damage and are predominantly repaired through either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways [3,4]. Homologous recombination is error-free and utilizes a homologous template (preferentially the sister chromatid) to repair the break. NHEJ is not dependent on a homologous sequence and can introduce errors due to modifications to the damaged ends prior to ligation. The Nijmegen breakage syndrome is one disorder that results from a mutation in a DSBR gene (NBS1). DNA double-strand breaks can arise from ionizing radiation exposure, chemical damage or normal cellular processes [3–5]. Improper or inefficient repair can result in the accumulation of damage, including microsatellite formation and chromosomal translocations

Abbreviations: SNP, single nucleotide polymorphism Corresponding author. Tel.: +1-250-472-4067; fax: +1-250-472-4075. E-mail address: [email protected] (B.W. Glickman). ∗

0027-5107/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 7 - 5 1 0 7 ( 0 2 ) 0 0 2 1 8 - X

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[5,6]. These forms of DNA damage are often observed in pre-cancerous and cancerous lesions [7]. Thus, factors that reduce DSBR efficiency may increase the risk of carcinogenesis.

paper compiles all population data reported to date on coding SNPs (cSNPs) in 24 double-strand break repair genes. Codon number, amino acid substitution, allele frequency and population data are reported for each SNP.

1.2. DNA repair and disease 1.3. Single nucleotide polymorphisms Defects in some DNA repair genes are known to affect disease predisposition, especially for certain forms of cancer [8,9]. For example, mutations in the mismatch repair genes hMSH2 and hMLH1 account for approximately 80% of hereditary non-polyposis colorectal cancer (HNPCC) cases [10,11]. Mutations in nucleotide excision repair genes can result in Xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy [12,13]. In order to investigate the possible connection between variants in DSBR genes and disease risk, this

Due to the degeneracy of the amino acid code, two-thirds of randomly generated base pair changes will alter the amino acid encoded. It has been noted, however, that only about half of the cSNPs observed in human populations are non-synonymous [14]. The decreased proportion in coding alterations suggests selective pressure against changes in protein primary structure. This effect may be attributed to negative consequences resulting from alteration of protein function. Rodent studies have shown that complete loss of

Table 1 Genes involved in DNA strand break repair pathways Gene symbol

Gene name

Protein function

BRCA1 BRCA2 DMC1 G22P1 (Ku 70) hHR21 (RAD21) LIG3

Breast cancer susceptibility gene 1 Breast cancer susceptibility gene 2 Dosage suppressor of mck1 homolog Ku 70 antigen—part of DNA-PK Rad21 (S. pombe) homolog DNA ligase 3

LIG4 MRE11A NBS1 PRKDC RAD50 RAD51 RAD51C RAD51L1 RAD51L3 RAD52 RAD54 (ATRX) RAD54B RAD54L XRCC1

DNA ligase 4 Meiotic recombination (S. cerevisiae) 11 homolog A Nijmegen breakage syndrome 1 Protein kinase, DNA-activated, catalytic polypeptide Rad50 (S. cerevisiae) homolog Rad51 (S. cerevisiae) homolog Rad51 (S. cerevisiae) homolog C Rad51-like enzyme 1 Rad51-like enzyme 3 Recombination protein RAD52 Rad54 (S. cerevisiae) homolog Rad54 (S. cerevisiae) homolog B Rad54 (S. cerevisiae) homolog X-ray repair complementing defective repair in Chinese hamster cells 1 X-ray repair complementing defective repair in Chinese hamster cells 2 X-ray repair complementing defective repair in Chinese hamster cells 3 X-ray repair complementing defective repair in Chinese hamster cells 4 X-ray repair complementing defective repair in Chinese hamster cells 5

Tumor suppressor Tumor suppressor Meiosis-specific recombinase ATP-dependent DNA helicase II Nuclear phospho-protein Complexes with XRCC3—required for break repair in G1 but not S phase Complexes with XRCC4 to bind and rejoin SSBs Part of MNR complex—binds ATP Part of MNR complex—binds ATP Catalytic subunit of serine/threonine kinase DNA-PK Part of MNR complex—binds ATP Complexes with ssDNA May assist RAD51 in interacting with DNA breaks Interacts with other RAD51 paralogs Interacts with other RAD51 paralogs Protects ssDNA from exonucleases Recombination protein Likely involved in recombination dsDNA-dependent ATPase Complexes with LIG3—required for break repair in G1 but not S phase Complexes with RAD51C and RAD51L3

XRCC2 XRCC3 XRCC4 XRCC5 (Ku 80)

Required for assembly/stabilization of RAD51 foci Complexes with Lig4 to bind and rejoin SSBs Ku 80 autoantigen, ATP-dependent DNA helicase II, part of DNA-PK

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

function in some DNA repair genes (e.g. ERCC1 [15]) has resulted in embryonic or developmental lethality. Allele frequency also appears to be dependent upon the nature of the substitution. In a study of SNPs in 106 genes, Cargill et al. [14] reported a gradation in average minor allele frequency: synonymous SNPs (14%), conservative SNPs (11%), and non-conservative SNPs (7%). Again, this indicates selection against amino acid changes. It should be noted that even silent mutations have been associated with alterations in phenotype. In ERCC1, the AAC/AAT polymorphism (N118N) affects cisplatin-DNA damage repair [16]. The 1215A/G polymorphism in the dopamine transporter gene DAT influences susceptibility to Parkinson’s disease [17]. Also, a S305S polymorphism in the tau gene (MAPT) results in the development of progressive supranuclear palsy [18]. Undoubtedly, some of the SNPs in DNA strand break repair genes will, to some extent, dictate individual differences in repair capabilities.

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2. Methods The list of genes involved in DNA strand break repair was derived from the Ronen and Glickman [1] and Wood et al. [2] papers. The NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP), JCIB SNP database (http://snp.ims.u-tokyo.ac.jp), University of Washington Genome Centre/Environmental Genome Project database (http://www.genome.washington.edu/ projects/egpsnps/), Human Genic Bi-Allelic SEquences (HGBASE) (http://hgbase.interactiva.de/), UCLADOE Laboratory for Structural Biology and Molecular Medicine (http://www.bioinformatics.ucla.edu/) and GeneSNPs (http://www.genome.utah.edu/genesnps/) databases were then searched for cSNPs in each of these genes. Each codon position was verified by comparison of the SNP and its flanking sequence with the appropriate NCBI mRNA reference sequence. A variant was added to the table only if the reported position corresponded with the NCBI RefSeq. For

Table 2 Total number of SNPs by gene in total and cancer-free populations Gene

Length of coding region (bp)

Total number of SNPs reported in all populations

Ratio (SNPs per bp)

Number of common SNPs in cancer-free populations

Ratio (SNPs per bp)

BRCA1 BRCA2 DMC1 G22P1 HHR21 LIG3 LIG4 MRE11A NBS1 PRKDC RAD50 RAD51 RAD51C RAD51L1 RAD51L3 RAD52 RAD54 RAD54B RAD54L XRCC1 XRCC2 XRCC3 XRCC4 XRCC5

5,592 10,257 1,023 1,830 1,896 2,769 2,535 2,127 2,265 12,387 3,939 1,019 1,131 1,053 986 1,260 7,479 2,733 1,434 1,902 843 1,041 1,011 2,199

120 65 1 1 2 4 15 11 12 0 10 3 0 0 0 2 8 5 0 31 1 1 2 4

0.0216 0.0063 0.0010 0.0005 0.0011 0.0014 0.0059 0.0052 0.0053 0 0.0025 0.0029 0 0 0 0.0016 0.0011 0.0018 0 0.0163 0.0012 0.0010 0.0020 0.0018

14 14 1 1 1 2 3 3 5 0 4 0 0 0 0 0 0 0 0 10 1 1 2 2

0.0025 0.0013 0.0010 0.0005 0.0005 0.0007 0.0012 0.0014 0.0022 0 0.0010 0 0 0 0 0 0 0 0 0.0053 0.0012 0.0010 0.0020 0.0009

Total

70,711

299

0.0042

64

0.0009

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Table 3 Coding SNPs in DNA strand break genes Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

Pop: 263 breast cancer patients Pop: 208 Seattle-area breast cancer patients Pop: 43 Singaporean breast cancer patients Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 208 Seattle-area breast cancer patients Pop: 90 African–American women Pop: 798 women from high-risk breast cancer families Pop: 46 Italian breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 10 breast/ovarian cancer patients Pop: 97 Italian breast/ovarian cancer patients Pop: 66 Polish breast/ovarian cancer families Pop: 70 Caucasian breast/ovarian cancer patients Pop: 208 Seattle-area breast cancer patients Pop: 798 women from high-risk breast cancer families Pop: 56 Japanese breast cancer patients Pop: 50 Norwegian breast/ovarian cancer patients Pop: 20 Italian breast cancer families Pop: 66 Polish breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 83 Spanish breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 20 Italian breast cancer families Pop: 112 British breast/ovarian cancer families. Note: T > G change in reference Pop: 798 women from high-risk breast cancer families Pop: 47 high-risk Jewish individuals Pop: 28 African–American breast cancer patients Pop: 61 cancer-free African–American individuals Pop: 798 women from high-risk breast cancer families Pop: 92 Chinese breast cancer patients and high-risk individuals Pop: 94 cancer-free, Caucasian women Pop: 216 Caucasian breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 91 Australian breast cancer patients Pop: 107 ovarian cancer patients

[19] [20] [21] [22]

BRCA1 BRCA1 BRCA1 BRCA1

1 18 38 38

0.004 0.005 0.093 N/R

G T G G

> > > >

T C A A

ATG (MET) > ATT (ILE) ATG (MET) > ACG (THR) AAG (LYS) > AAA (LYS) AAG (LYS) > AAA (LYS)

BRCA1 BRCA1 BRCA1

38 38 38

0.005 0.01 0.001

G > A G > A G > A

AAG (LYS) > AAA (LYS) AAG (LYS) > AAA (LYS) AAG (LYS) > AAA (LYS)

BRCA1 BRCA1

39 60

0.011 0.001

G > A C > T

TGT (CYS) > TAT (TYR) CAG (GLN) > TAG (stop)

BRCA1 BRCA1 BRCA1 BRCA1

61 61 61 61

0.050 0.021 0.053 0.007

T T T T

TGT TGT TGT TGT

BRCA1 BRCA1

61 61

0.005 0.001

T > G T > G

TGT (CYS) > GGT (GLY) TGT (CYS) > GGT (GLY)

BRCA1 BRCA1

63 64

0.035 0.010

T > A T > G

TTA (LEU) > TAA (stop) TGT (CYS) > GGT (GLY)

BRCA1 BRCA1 BRCA1

64 64 64

0.025 0.008 0.001

T > C T > C G > A

TGT (CYS) > CGT (ARG) TGT (CYS) > CGT (ARG) TGT (CYS) > TAT (TYR)

BRCA1

71

0.006

A > G

AGG (ARG) > GGG (GLY)

BRCA1

87

0.001

T > G

TTG (LEU) > GTG (VAL)

BRCA1

143

0.001

G > T

GAA (GLU) > TAA (stop)

BRCA1 BRCA1

158 169

0.025 0.004

A > T C > T

AAC (ASN) > TAC (TYR) CAG (GLN) > TAG (stop)

BRCA1

179

0.002

A > G

TAC (TYR) > TGC (CYS)

BRCA1 BRCA1

179 186

0.011 0.018

A > G C > A

TAC (TYR) > TGC (CYS) TCT (SER) > TAT (TYR)

BRCA1

186

0.008

C > A

TCT (SER) > TAT (TYR)

BRCA1

191

0.001

G > A

GTT (VAL) > ATT (ILE)

BRCA1

191

0.005

G > A

GTT (VAL) > ATT (ILE)

BRCA1 BRCA1

197 197

0.021 0.004

C > T C > T

TGC (CYS) > TGT (CYS) TGC (CYS) > TGT (CYS)

BRCA1

197

0.007

C > T

TGC (CYS) > TGT (CYS)

BRCA1

204

0.001

G > C

TTG (LEU) > TTC (PHE)

BRCA1

213

0.003

A > G

BRCA1

227

0.01

G > A

AGG Note: GAA Note:

> > > >

G G G G

(CYS) (CYS) (CYS) (CYS)

> > > >

GGT GGT GGT GGT

(GLY) (GLY) (GLY) (GLY)

(ARG) > GGG (GLY). Asp > Gly in reference (GLU) > AAA (LYS). Gln > Lys in reference

[20] [23] [25] [26] [25] [27] [28] [29] [30] [20] [25] [31] [32] [33] [29] [25] [34] [25] [25] [33] [35] [25] [36] [37] [37] [25] [38] [39] [39] [30] [25] [40] [41]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

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Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

271

0.001

G > A

GTG (VAL) > ATG (MET)

[42]

BRCA1

271

0.001

G > C

GTG (VAL) > CTG (LEU)

BRCA1

298

0.020

T > C

AAT (ASN) > AAC (ASN)

BRCA1

321

0.001

G > A

TGG (TRP) > stop

BRCA1 BRCA1 BRCA1

327 327 327

0.005 0 0.002

A > G A > G A > G

ACA (THR) > ACG (THR) ACA (THR) > ACG (THR) ACA (THR) > ACG (THR)

BRCA1

346

0.055

C > T

CCC (PRO) > TCC (SER)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

356 356 356 356 356

0.053 0.076 0.070 0.060 0.058

A A A A A

CAG CAG CAG CAG CAG

BRCA1 BRCA1

356 356

0.06 0.121

A > G A > G

CAG (GLN) > CGG (ARG) CAG (GLN) > CGG (ARG)

BRCA1 BRCA1 BRCA1 BRCA1

356 356 356 356

0.18 0.15 0.07 0.05

A A A A

CAG CAG CAG CAG

BRCA1

356

0.062

A > G

CAG (GLN) > CGG (ARG)

BRCA1 BRCA1 BRCA1 BRCA1

356 356 356 372

0.011 0.066 0.045 0.001

A A A G

CAG CAG CAG TGG

BRCA1

374

0.006

C > T

ACA (THR) > ATA (ILE)

BRCA1 BRCA1

379 467

0.005 0.001

T > G A > T

ATT (ILE) > ATG (MET) AAG (LYS) > TAG (stop)

BRCA1

484

0.020

G > T

GGA (GLY) > TGA (stop)

BRCA1

486

0.002

T > C

TTT (PHE) > CTT (LEU)

BRCA1 BRCA1

486 489

0.011 0.005

T > C G > T

TTT (PHE) > CTT (LEU) GAG (GLU) > TAG (stop)

BRCA1

496

0.007

G > A

CGT (ARG) > CAT (HIS)

BRCA1

504

0.001

G > A

CGT (ARG) > CAT (HIS)

BRCA1

539

0.007

G > A

ACG (THR) > ACA (THR)

BRCA1

550

0.002

A > C

AAT (ASN) > CAT (HIS)

BRCA1 BRCA1

550 563

0.011 0.007

A > C C > T

AAT (ASN) > CAT (HIS) CAG (GLN) > TAG (stop)

Pop: 103 Japanese breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 50 Turkish breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 208 Seattle-area breast cancer patients Pop: 182 cancer-free Caucasian individuals Pop: 798 women from high-risk breast cancer families Pop: found in 1 of 18 Taiwanese breast cancer families Pop: 765 British breast cancer patients Pop: 230 British ovarian cancer patients Pop: 631 cancer-free British women Pop: 83 cancer-free, Caucasian women Pop: 173 Caucasian breast/ovarian cancer patients Pop: 1378 British breast cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 26 Cypriot breast cancer families Pop: 218 cancer-free Cypriot individuals Pop: 91 non-Hispanic ovarian cancer patients Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 162 cancer-free individuals. Note: codon 317 in reference Pop: 47 high-risk Jewish individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 798 women from high-risk breast cancer families Pop: 83 Spanish breast/ovarian cancer families Pop: 199 cancer-free Seattle-area individuals Pop: 798 women from high-risk breast cancer families Pop: 50 Norwegian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 47 high-risk Jewish individuals Pop: 94 American ovarian cancer patients (somatic mutation) Pop: 70 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 70 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 47 high-risk Jewish individuals Pop: 70 Caucasian breast/ovarian cancer patients

> > > > >

> > > >

> > > >

G G G G G

G G G G

G G G A

(GLN) (GLN) (GLN) (GLN) (GLN)

(GLN) (GLN) (GLN) (GLN)

> > > > >

> > > >

CGG CGG CGG CGG CGG

CGG CGG CGG CGG

(ARG) (ARG) (ARG) (ARG) (ARG)

(ARG) (ARG) (ARG) (ARG)

(GLN) > CGG (ARG) (GLN) > CGG (ARG) (GLN) > CGG (ARG) (TRP) > stop

[25] [43] [25] [20] [24] [25] [22] [44] [44] [44] [39] [39] [45] [30] [46] [46] [41] [47] [48] [36] [40] [40] [25] [34] [20] [25] [32] [25] [36] [49] [30] [25] [30] [25] [36] [30]

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Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

563

0.011

C > T

CAG (GLN) > TAG (stop)

[26]

BRCA1

563

0.001

C > T

CAG (GLN) > TAG (stop)

BRCA1

607

0.004

A > T

AAA (LYS) > TAA (stop)

BRCA1

622

0.001

G > A

GCG (ALA) > GCA (ALA)

BRCA1

654

0.010

A > G

AAG (LYS) > GAG (GLU)

BRCA1

668

0.001

C > T

CTC (LEU) > TTC (PHE)

BRCA1

679

0.001

A > T

AAG (LYS) > TAG (stop)

BRCA1 BRCA1

693 693

0.038 0.069

G > A G > A

GAC (ASP) > AAC (ASN) GAC (ASP) > AAC (ASN)

BRCA1

693

0.079

G > A

GAC (ASP) > AAC (ASN)

BRCA1 BRCA1 BRCA1 BRCA1

693 693 694 694

0.010 0.011 0.244 0.315

G G C C

GAC GAC AGC AGC

BRCA1

694

0.221

C > T

AGC (SER) > AGT (SER)

BRCA1 BRCA1

694 694

0.256 N/R

C > T C > T

AGC (SER) > AGT (SER) AGC (SER) > AGT (SER)

BRCA1

694

0.10

C > T

AGC (SER) > AGT (SER)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

694 694 694 694 694 727

0.020 0.010 0.011 0.220 0.313 0.001

C C C C C C

AGC AGC AGC AGC AGC CCA

BRCA1 BRCA1 BRCA1

770 771 771

0.011 0.300 0.319

C > A T > C T > C

TCA (SER) > TGA (stop) TTG (LEU) > CTG (LEU) TTG (LEU) > CTG (LEU)

BRCA1

771

0.386

T > C

TTG (LEU) > CTG (LEU)

BRCA1

771

0.528

T > C

TTG (LEU) > CTG (LEU)

BRCA1 BRCA1 BRCA1 BRCA1

771 771 771 771

0.441 0.334 0.024 N/R

T T T T

TTG TTG TTG TTG

BRCA1

771

0.1

T > C

TTG (LEU) > CTG (LEU)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

771 771 771 771 771

0.35 0.16 0.011 0.220 0.313

T T T T T

TTG TTG TTG TTG TTG

Pop: 46 Italian breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 112 British breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 50 Turkish breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 78 cancer-free, Caucasian women Pop: 364 Caucasian breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 50 Turkish breast/ovarian cancer patients Pop: 47 high-risk Jewish individuals Pop: 78 cancer-free, Caucasian women Pop: 352 Caucasian breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 31 individuals of various ethnicity Pop: 50 Turkish breast/ovarian cancer patients Pop: 47 high-risk Jewish individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 798 women from high-risk breast cancer families Pop: 46 Italian breast/ovarian cancer families Pop: 94 cancer-free, Caucasian women Pop: 144 Caucasian breast/ovarian cancer patients Pop: 22 non-Jewish, Iranian breast cancer patients Pop: 18 non-Jewish, cancer-free Iranian women Pop: 43 Singaporean breast cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 21 known BRCA1-variant samples Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 640 Japanese samples Pop: 25 individuals of various ethnicity Pop: 47 high-risk Jewish individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women

> > > >

> > > > > >

> > > >

> > > > >

A A T T

T T T T T T

C C C C

C C C C C

(ASP) (ASP) (SER) (SER)

(SER) (SER) (SER) (SER) (SER) (PRO)

(LEU) (LEU) (LEU) (LEU)

(LEU) (LEU) (LEU) (LEU) (LEU)

> > > >

> > > > > >

> > > >

> > > > >

AAC AAC AGT AGT

AGT AGT AGT AGT AGT CTA

CTG CTG CTG CTG

CTG CTG CTG CTG CTG

(ASN) (ASN) (SER) (SER)

(SER) (SER) (SER) (SER) (SER) (LEU)

(LEU) (LEU) (LEU) (LEU)

(LEU) (LEU) (LEU) (LEU) (LEU)

[25] [35] [25] [43] [25] [25] [39] [39] [30] [43] [36] [39] [39] [30] [41] [22] [47] [23,50] [43] [36] [40] [40] [25] [26] [39] [39] [51] [51] [21] [41] [52] [22] [47] [53] [50] [36] [40] [40]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

181

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

Pop: 50 Norwegian breast/ovarian cancer patients Pop: 45 individuals from breast/ovarian cancer families Pop: 70 Caucasian breast/ovarian cancer patients Pop: 50 Norwegian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 70 Caucasian breast/ovarian cancer patients Pop: 305 Californian breast cancer and 79 ovarian cancer patients Pop: 413 Californian breast and ovarian cancer patients Pop: 156 cancer-free, Caucasian women Pop: 302 Caucasian breast/ovarian cancer patients Pop: 107 ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 97 Italian breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 801 British breast cancer patients Pop: 223 British ovarian cancer patients Pop: 572 cancer-free British women Pop: 113 cancer-free, Caucasian women Pop: 107 Caucasian breast/ovarian cancer patients Pop: 22 non-Jewish, Iranian breast cancer patients Pop: 18 non-Jewish, cancer-free Iranian women Pop: 1314 British breast cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 155 cancer-free Caucasian individuals. Note: codon 878 in reference Pop: 23 individuals of various ethnicity Pop: 50 Turkish breast/ovarian cancer patients Pop: 47 high-risk Jewish individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 50 Norwegian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families

[32]

BRCA1

772

0.010

T > C

GTA (VAL) > GCA (ALA)

BRCA1

780

0.011

C > T

CAG (GLN) > TAG (stop)

BRCA1

804

0.007

G > C

CAG (GLN) > CAC (HIS)

BRCA1

820

0.010

A > G

AAA (LYS) > GAA (GLU)

BRCA1

820

0.002

A > G

AAA (LYS) > GAA (GLU)

BRCA1

826

0.007

C > A

ACA (THR) > AAA (LYS)

BRCA1

841

0.004

C > T

CGG (ARG) > TGG (TRP)

BRCA1

841

0.002

C > T

CGG (ARG) > TGG (TRP)

BRCA1 BRCA1

841 841

0.006 0.003

C > T C > T

CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP)

BRCA1 BRCA1

841 841

0.005 0.001

C > T C > T

CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP)

BRCA1 BRCA1

864 866

0.005 0.007

C > G C > T

TCA (SER) > TGA (stop) CGC (ARG) > TGC (CYS)

BRCA1

866

0.001

C > T

CGC (ARG) > TGC (CYS)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

871 871 871 871 871

0.342 0.332 0.316 0.279 0.420

C C C C C

CCG CCG CCG CCG CCG

BRCA1

871

0.386

C > T

CCG (PRO) > CTG (LEU)

BRCA1

871

0.556

C > T

CCG (PRO) > CTG (LEU)

BRCA1 BRCA1

871 871

0.33 0.114

C > T C > T

CCG (PRO) > CTG (LEU) CCG (PRO) > CTG (LEU)

BRCA1 BRCA1

871 871

0.396 N/R

C > T C > T

CCG (PRO) > CTG (LEU) CCG (PRO) > CTG (LEU)

BRCA1

871

0.10

C > T

CCG (PRO) > CTG (LEU)

BRCA1

871

N/R

C > T

CCG (PRO) > CTG (LEU)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

871 871 871 871 871 908

0.46 0.030 0.011 0.214 0.299 0.010

C C C C C G

CCG CCG CCG CCG CCG GAA

BRCA1 BRCA1

911 911

0 0.002

A > G A > G

GGA (GLY) > GGG (GLY) GGA (GLY) > GGG (GLY)

BRCA1

938

0.001

A > G

CCA (PRO) > CCG (PRO)

> > > > >

> > > > > >

T T T T T

T T T T T T

(PRO) (PRO) (PRO) (PRO) (PRO)

> > > > >

CTG CTG CTG CTG CTG

(LEU) (LEU) (LEU) (LEU) (LEU)

(PRO) > CTG (LEU) (PRO) > CTG (LEU) (PRO) > CTG (LEU) (PRO) > CTG (LEU) (PRO) > CTG (LEU) (GLN) > TAA (stop)

[54] [30] [32] [25] [30] [55] [55] [39] [39] [41] [25] [28] [30] [25] [44] [44] [44] [39] [39] [51] [51] [45] [30] [41] [22] [47] [48] [50] [43] [36] [40] [40] [32] [41] [25] [25]

182

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

Pop: 94 American ovarian cancer patients (somatic mutation) Note: found in two Jewish non-Ashkenazi Iraqi ovarian cancer patients Pop: 118 cancer-free Iraqi individuals Pop: 88 cancer-free, Caucasian women Pop: 194 Caucasian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 47 high-risk Jewish individuals. Note: listed as codon 1007 in reference Pop: 798 women from high-risk breast cancer families Pop: 84 cancer-free, Caucasian women Pop: 234 Caucasian breast/ovarian cancer patients Pop: 22 non-Jewish, Iranian breast cancer patients Pop: 18 non-Jewish, cancer-free Iranian women Pop: 70 Caucasian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 21 known BRCA1-variant samples Pop: 18 Taiwanese breast cancer families Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 27 individuals of various ethnicity Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 50 Norwegian breast/ovarian cancer patients Pop: 82 cancer-free, Caucasian women Pop: 242 Caucasian breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 208 Seattle-area breast cancer patients Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 92 Chinese breast cancer patients and high-risk individuals Pop: 91 Australian breast cancer patients

[49]

BRCA1

957

0.005

C > T

CAG (GLN) > TAG (stop)

BRCA1

978

N/A

T > G

TAT (TYR) > TAG (stop)

BRCA1 BRCA1 BRCA1

978 1008 1008

0 0 0.005

T > G G > A G > A

TAT (TYR) > TAG (stop) ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE)

BRCA1 BRCA1

1008 1008

0 0.001

G > A G > A

ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE)

BRCA1

1008

0.011

G > A

ATG (MET) > ATA (ILE)

BRCA1

1028

0.001

G > A

CGT (ARG) > CAT (HIS)

BRCA1 BRCA1

1038 1038

0.238 0.342

A > G A > G

GAA (GLU) > GGA (GLY) GAA (GLU) > GGA (GLY)

BRCA1

1038

0.432

A > G

GAA (GLU) > GGA (GLY)

BRCA1

1038

0.556

A > G

GAA (GLU) > GGA (GLY)

BRCA1

1038

0.186

A > G

GAA (GLU) > GGA (GLY)

BRCA1 BRCA1 BRCA1 BRCA1

1038 1038 1038 1038

0.355 0.024 N/R 0.100

A A A A

> > > >

G G G G

GAA GAA GAA GAA

(GLU) (GLU) (GLU) (GLU)

BRCA1 BRCA1 BRCA1 BRCA1

1038 1038 1038 1040

0.02 0.132 0.321 0.010

A A A G

> > > >

G G G A

GAA GAA GAA AGC

(GLU) > GGA (GLY) (GLU) > GGA (GLY) (GLU) > GGA (GLY) (SER) > AAC (ASN)

BRCA1 BRCA1

1040 1040

0.037 0.029

G > A G > A

AGC (SER) > AAC (ASN) AGC (SER) > AAC (ASN)

BRCA1

1040

0.021

G > A

AGC (SER) > AAC (ASN)

BRCA1 BRCA1

1040 1040

0.005 0.05

G > A G > A

AGC (SER) > AAC (ASN) AGC (SER) > AAC (ASN)

BRCA1

1040

0.005

G > A

AGC (SER) > AAC (ASN)

BRCA1

1040

0.011

G > A

BRCA1 BRCA1

1041 1060

0.02 0.001

A > G G > T

AGC (SER) > AAC (ASN). Note: codon 1039 in reference AGT (SER) > GGT (GLY) GAA (GLU) > TAA (stop)

BRCA1

1140

0.018

A > G

AGT (SER) > GGT (GLY)

BRCA1

1140

0.028

A > G

AGT (SER) > GGT (GLY)

BRCA1

1142

0.001

G > C

GCA (ALA) > CCA (PRO)

BRCA1

1150

0.005

C > T

CCT (PRO) > TCT (SER)

BRCA1

1183

0.320

A > G

AAA (LYS) > AGA (ARG)

> > > >

GGA GGA GGA GGA

(GLY) (GLY) (GLY) (GLY)

Pop: 31 individuals of various ethnicity Pop: 798 women from high-risk breast cancer families Pop: 28 African–American breast cancer patients Pop: 54 African–American breast cancer patients Pop: 798 women from high-risk breast cancer families Pop: 103 Japanese breast/ovarian cancer patients Pop: 156 cancer-free, Caucasian women

[56] [56] [39] [39] [41] [25] [36] [25] [39] [39] [51] [51] [30] [41] [52] [22] [47] [50] [40] [40] [32] [39] [39] [30] [20] [47] [38] [40] [57] [25] [37] [58] [25] [42] [39]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

183

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

1183

0.313

A > G

AAA (LYS) > AGA (ARG)

[39]

BRCA1

1183

0.409

A > G

AAA (LYS) > AGA (ARG)

BRCA1

1183

0.500

A > G

AAA (LYS) > AGA (ARG)

BRCA1

1183

0.207

A > G

AAA (LYS) > AGA (ARG)

BRCA1 BRCA1 BRCA1

1183 1183 1183

0.371 0.024 N/R

A > G A > G A > G

AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG)

BRCA1

1183

0.10

A > G

AAA (LYS) > AGA (ARG)

BRCA1

1183

0.33

A > G

AAA (LYS) > AGA (ARG)

BRCA1 BRCA1 BRCA1

1183 1183 1183

0.125 0.160 0.009

A > G A > G A > G

AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG)

BRCA1 BRCA1

1183 1183

0.160 0.011

A > G A > G

AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG)

BRCA1 BRCA1 BRCA1

1183 1183 1196

0.209 0.313 0.001

A > G A > G C > A

AAA (LYS) > AGA (ARG) AAA (LYS) > AGA (ARG) ACA (THR) > AAA (LYS)

BRCA1 BRCA1

1203 1214

0.007 0.010

C > T G > T

CGA (ARG) > TGA (stop) GAG (GLU) > TAG (stop)

BRCA1 BRCA1

1219 1219

0 0.007

G > C G > C

GAG (GLU) > GAC (ASP) GAG (GLU) > GAC (ASP)

BRCA1

1238

0.001

C > T

CCT (PRO) > CTT (LEU)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

1239 1250 1250 1250 1250

0.03 0.004 0.024 0.005 0.001

G G G G G

CAG GAG GAG GAG GAG

BRCA1

1297

0.009

C > T

TCT (SER) > TTT (PHE)

BRCA1

1323

0.063

C > T

CAA (GLN) > TAA (stop)

BRCA1

1323

0

C > T

CAA (GLN) > TAA (stop)

BRCA1 BRCA1 BRCA1

1342 1347 1347

0.005 0 0.007

A > G A > G A > G

TCA (SER) > TCG (SER) AGA (ARG) > GGA (GLY) AGA (ARG) > GGA (GLY)

BRCA1 BRCA1

1347 1347

0.005 0.009

A > G A > G

AGA (ARG) > GGA (GLY) AGA (ARG) > GGA (GLY)

BRCA1 BRCA1 BRCA1

1395 1395 1395

0.030 0.030 0.007

C > T G > A G > A

CAG (GLN) > TAG (stop) CAG (GLN) > CAA (GLN) CAG (GLN) > CAA (GLN)

BRCA1

1395

0.005

C > T

CAG (GLN) > TAG (stop)

Pop: 182 Caucasian breast/ovarian cancer patients Pop: 22 non-Jewish, Iranian breast cancer patients Pop: 18 non-Jewish, cancer-free Iranian women Pop: 70 Caucasian breast/ovarian cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 21 known BRCA1-variant samples Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 163 cancer-free Caucasian controls. Note: codon 1190 in reference Pop: 32 individuals of various ethnicity Pop: 50 Turkish breast/ovarian cancer patients Pop: 54 African–American breast cancer patients Pop: 47 high-risk Jewish individuals Pop: 92 Chinese breast cancer patients and high-risk individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 798 women from high-risk breast cancer families Pop: 76 Japanese ovarian cancer patients Pop: 103 Japanese breast/ovarian cancer patients Pop: 64 cancer-free, Caucasian women Pop: 144 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 17 peritoneal carcinoma patients Pop: 263 breast cancer patients Pop: 21 known BRCA1-variant samples Pop: 208 Seattle-area breast cancer patients Pop: 798 women from high-risk breast cancer families Pop: 54 African–American breast cancer patients Pop: eight breast cancer kindreds. Note: codon 1313 in reference Pop: 170 cancer-free Caucasian controls. Note: codon 1313 in reference Pop: 208 Seattle-area breast cancer patients Pop: 232 cancer-free, Caucasian women Pop: 144 Caucasian breast/ovarian cancer patients Pop: 208 Seattle-area breast cancer patients Pop: 798 women from high-risk breast cancer families Pop: 17 breast/ovarian cancer patients Pop: 17 breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 208 Seattle-area breast cancer patients

> > > > >

C T T T T

(GLN) (GLU) (GLU) (GLU) (GLU)

> > > > >

CAC TAG TAG TAG TAG

(HIS) (stop) (stop) (stop) (stop)

[51] [51] [30] [41] [52] [22] [47] [48] [57] [43] [58] [36] [38] [40] [40] [25] [59] [42] [39] [39] [25] [60] [19] [52] [20] [25] [58] [48] [48] [20] [39] [39] [20] [25] [27] [27] [30] [20]

184

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

1395

0.001

C > T

CAG (GLN) > TAG (stop)

[25]

BRCA1 BRCA1

1406 1408

0.02 0.001

G > T C > T

AAG (LYS) > AAT (ASN) CAG (GLN) > TAG (stop)

BRCA1

1421

0.001

C > T

CAT (HIS) > TAT (TYR)

BRCA1 BRCA1

1429 1431

0.005 0.10

C > A T > C

TAC (TYR) > TAA (stop) TCC (SER) > CCC (PRO)

BRCA1 BRCA1

1436 1436

0.224 0.35

T > C T > C

TCT (SER) > TCC (SER) TCT (SER) > TCC (SER)

BRCA1 BRCA1

1436 1436

0.331 0.303

T > C T > C

TCT (SER) > TCC (SER) TCT (SER) > TCC (SER)

BRCA1

1436

0.386

T > C

TCT (SER) > TCC (SER)

BRCA1

1436

0.500

T > C

TCT (SER) > TCC (SER)

BRCA1

1436

0.214

T > C

TCT (SER) > TCC (SER)

BRCA1 BRCA1 BRCA1

1436 1436 1436

0.453 0.332 N/R

T > C T > C T > C

TCT (SER) > TCC (SER) TCT (SER) > TCC (SER) TCT (SER) > TCC (SER)

BRCA1

1436

0.10

T > C

TCT (SER) > TCC (SER)

BRCA1

1436

0.335

T > C

TCT (SER) > TCC (SER)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

1436 1436 1436 1436 1443

0.20 0.04 0.214 0.313 0.010

T C T T C

TCT (SER) > TCC (SER) TCT (SER) > TCC (SER) TCT (SER) > TCC (SER) TCT (SER) > TCC (SER) CGA (ARG) > TGA (stop)

BRCA1

1443

0.010

C > G

CGA (ARG) > GGA (GLY)

BRCA1 BRCA1

1443 1443

0.005 0.004

C > T C > T

CGA (ARG) > TGA (stop) CGA (ARG) > TGA (stop)

BRCA1 BRCA1

1443 1443

0.024 0.002

C > T C > T

CGA (ARG) > TGA (stop) CGA (ARG) > TGA (stop)

BRCA1

1443

0.001

C > G

CGA (ARG) > GGA (GLY)

BRCA1

1443

0.005

C > T

CGA (ARG) > TGA (stop)

BRCA1

1495

0.002

G > T

AGG (ARG) > ATG (MET)

BRCA1

1512

0.010

G > T

AGT (SER) > ATT (ILE)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

1512 1512 1512 1512 1512

0.067 0.019 0 0.005 0.008

G G G G G

AGT AGT AGT AGT AGT

BRCA1

1512

0.005

G > T

Pop: 798 women from high-risk breast cancer families Pop: 107 ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 97 Italian breast/ovarian cancer patients Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 29 breast/ovarian cancer patients Pop: 83 Spanish breast/ovarian cancer families and 100 cancer-free controls Pop: 166 cancer-free, Caucasian women Pop: 238 Caucasian breast/ovarian cancer patients Pop: 22 non-Jewish, Iranian breast cancer patients Pop: 18 non-Jewish, cancer-free Iranian women Pop: 70 Caucasian breast/ovarian cancer patients Pop: 43 Singaporean breast cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 173 cancer-free Caucasian individuals. Note: codon 1443 in reference Pop: EST assembly Pop: 14 individuals of various ethnicity Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 50 Norwegian breast/ovarian cancer patients Pop: 50 Norwegian breast/ovarian cancer patients Pop: 97 Italian breast/ovarian cancer patients Pop: 112 British breast/ovarian cancer families Pop: 21 known BRCA1-variant samples Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 92 Chinese breast cancer patients and high-risk individuals Pop: 798 women from high-risk breast cancer families Pop: 50 Norwegian breast/ovarian cancer patients Pop: 15 breast/ovarian cancer patients Pop: 26 Cypriot breast cancer families Pop: 218 cancer-free Cypriot individuals Pop: 107 ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 91 Australian breast cancer patients. Note: listed as codon 1845 in reference

> > > > >

> > > > >

C T C C T

T T T T T

(SER) (SER) (SER) (SER) (SER)

> > > > >

ATT ATT ATT ATT ATT

(ILE) (ILE) (ILE) (ILE) (ILE)

AGT (SER) > ATT (ILE)

[41] [25] [25] [28] [47] [27] [34] [39] [39] [51] [51] [30] [21] [41] [22] [47] [48] [61] [50] [40] [40] [32] [32] [28] [35] [52] [25] [25] [38] [25] [32] [27] [46] [46] [41] [25] [40]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

185

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

1534

0.001

G > A

GTG (VAL) > ATG (MET)

[51]

BRCA1

1534

0.001

G > A

GTG (VAL) > ATG (MET)

BRCA1 BRCA1 BRCA1

1548 1561 1561

0.033 0 0.003

G > A C > T C > T

ACG (THR) > ACA (THR) ACC (THR) > ATC (ILE) ACC (THR) > ATC (ILE)

BRCA1

1563

0.001

C > G

TAC (TYR) > TAG (stop)

BRCA1

1604

0.007

A > G

CAA (GLN) > CAG (GLN)

BRCA1

1604

0.001

A > G

CAA (GLN) > CAG (GLN)

BRCA1 BRCA1

1613 1613

0.207 0.35

A > G A > G

AGT (SER) > GGT (GLY) AGT (SER) > GGT (GLY)

BRCA1 BRCA1

1613 1613

0.311 0.317

A > G A > G

AGT (SER) > GGT (GLY) AGT (SER) > GGT (GLY)

BRCA1

1613

0.386

A > G

AGT (SER) > GGT (GLY)

BRCA1

1613

0.528

A > G

AGT (SER) > GGT (GLY)

BRCA1

1613

0.179

A > G

AGT (SER) > GGT (GLY)

BRCA1 BRCA1 BRCA1

1613 1613 1613

0.547 0.355 N/R

A > G A > G A > G

AGT (SER) > GGT (GLY) AGT (SER) > GGT (GLY) AGT (SER) > GGT (GLY)

BRCA1

1613

0.10

A > G

AGT (SER) > GGT (GLY)

BRCA1

1613

0.310

A > G

AGT (SER) > GGT (GLY)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

1613 1613 1613 1613 1613 1628 1628

0.33 0.17 0.011 0.220 0.313 0 0.003

A A A A A A A

AGT AGT AGT AGT AGT ATG ATG

BRCA1 BRCA1

1628 1637

0.005 0.010

A > G C > T

ATG (MET) > GTG (VAL) CCA (PRO) > CTA (LEU)

BRCA1 BRCA1

1641 1652

0.005 0.020

G > C G > A

GCT (ALA) > CCT (PRO) ATG (MET) > ATA (ILE)

BRCA1 BRCA1

1652 1652

0.061 0.029

G > A G > A

ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE)

BRCA1 BRCA1 BRCA1

1652 1652 1652

N/R 0.02 0.025

G > A G > A G > A

ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE)

BRCA1 BRCA1 BRCA1

1652 1652 1692

0.019 0.007 0.02

G > A G > A G > A

ATG (MET) > ATA (ILE) ATG (MET) > ATA (ILE) GAT (ASP) > AAT (ASN)

Pop: 80 non-Jewish Iranian breast cancer patients Pop: 798 women from high-risk breast cancer families Pop: 15 breast/ovarian cancer patients Pop: 240 cancer-free, Caucasian women Pop: 308 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 70 Caucasian breast/ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 41 breast/ovarian cancer patients Pop: 83 Spanish breast/ovarian cancer patients and 100 cancer-free controls. Note: codon 1612 in reference Pop: 164 cancer-free, Caucasian women Pop: 356 Caucasian breast/ovarian cancer patients Pop: 80 non-Jewish Iranian breast cancer patients. Note: codon 1612 in reference Pop: 18 non-Jewish, cancer-free Iranian women. Note: codon 1612 in reference Pop: 70 Caucasian breast/ovarian cancer patients Pop: 43 Singaporean breast cancer patients Pop: 91 non-Hispanic ovarian cancer patients Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 20 PTT-negative Bulgarian breast cancer patients Pop: 168 cancer-free Caucasian controls. Note: codon 1619 in reference Pop: Finnish breast cancer families Pop: 32 individuals of various ethnicity Pop: 47 high-risk Jewish individuals Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 92 cancer-free, Caucasian women Pop: 376 Caucasian breast/ovarian cancer patients Pop: 199 cancer-free Seattle-area individuals Pop: 50 Norwegian breast/ovarian cancer patients Pop: 107 ovarian cancer patients Pop: 50 Norwegian breast/ovarian cancer patients Pop: 41 breast/ovarian cancer patients Pop: 70 Caucasian breast/ovarian cancer patients Pop: 88 Finnish breast cancer families Pop: 32 individuals of various ethnicity Pop: 798 women from high-risk breast cancer families Pop: 91 Australian breast cancer patients Pop: 67 cancer-free Australian women Pop: 107 ovarian cancer patients

> > > > > > >

G G G G G G G

(SER) > GGT (GLY) (SER) > GGT (GLY) (SER) > GGT (GLY) (SER) > GGT (GLY) (SER) > GGT (GLY) (MET) > GTG (VAL) (MET) > GTG (VAL)

[25] [27] [39] [39] [25] [30] [25] [27] [34]

[39] [39] [51] [51] [30] [21] [41] [22] [47] [48] [24] [57] [36] [40] [40] [39] [39] [20] [32] [41] [32] [27] [30] [62] [50] [25] [40] [40] [41]

186

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA1

1694

0.001

G > T

GAG (GLU) > TAG (stop)

[25]

BRCA1 BRCA1

1708 1715

0.024 0.006

C > A G > A

GCG (ALA) > GAG (GLU) AGC (SER) > AAC (ASN)

BRCA1

1718

0.001

G > A

TGG (TRP) > stop

BRCA1

1738

0.001

G > A

GGA (GLY) > GAA (GLU)

BRCA1

1739

0.001

A > G

GAT (ASP) > GGT (GLY)

BRCA1 BRCA1

1749 1749

0 0.004

C > G C > G

CCA (PRO) > CGA (ARG) CCA (PRO) > CGA (ARG)

BRCA1

1751

0.001

C > T

CGA (ARG) > TGA (stop)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1

1775 1775 1775 1776 1804

0.024 0.063 0 0.005 0.001

T T T C T

ATG ATG ATG CCA GTC

BRCA1

1806

0.001

C > A (G?)

CCA (PRO) > ALA?

BRCA1 BRCA1

1812 1835

0.005 0.004

C > T C > T

CCA (PRO) > TCA (SER) CGA (ARG) > TGA (stop)

BRCA1

1835

0.009

C > T

CGA (ARG) > TGA (stop)

BRCA1

1837

0.036

T > C

TGG (TRP) > CGG (ARG)

Pop: 798 women from high-risk breast cancer families Pop: 21 known BRCA1-variant samples Pop: 83 Spanish breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 173 British, cancer-free individuals Pop: 112 British breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 21 known BRCA1-variant samples Pop: eight breast cancer kindreds Pop: 120 cancer-free Caucasian controls Pop: 107 ovarian cancer patients Pop: 798 women from high-risk breast cancer families Pop: 798 women from high-risk breast cancer families Pop: 107 ovarian cancer patients Pop: 112 British breast/ovarian cancer families Pop: 798 women from high-risk breast cancer families Pop: 14 breast/ovarian cancer patients

BRCA2

108

0.018

A > C

AAT (ASN) > CAT (HIS)

BRCA2

108

0

A > C

AAT (ASN) > CAT (HIS)

BRCA2

118

0.009

G > A

CGC (ARG) > CAC (HIS)

BRCA2

172

0.008

G > T

AAG (LYS) > AAT (ASN)

BRCA2

194

0.013

G > A

TGG (TRP) > TAG (stop)

BRCA2

289

0.033

A > C

ASN (AAT) > HIS (CTT)

BRCA2 BRCA2

289 289

0.026 N/R

A > C A > C

ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

289 289 289 289 315

0.060 0.14 0 0.05 0.009

A A A A T

ASN ASN ASN ASN TGT

BRCA2 BRCA2 BRCA2

372 372 372

0.216 0.303 0.150

A > C A > C A > C

ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT)

BRCA2

372

N/A

A > C

ASN (AAT) > HIS (CTT)

BRCA2 BRCA2

372 372

0.265 0.269

A > C A > C

ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT)

> > > > >

> > > > >

G G G T A

C C C C A

(MET) > AGG (ARG) (MET) > AGG (ARG) (MET) > AGG (ARG) (PRO) > TCA (SER) (VAL) > GAC (ASP)

(AAT) (AAT) (AAT) (AAT) (CYS)

> > > > >

HIS (CTT) HIS (CTT) HIS (CTT) HIS (CTT) AGT (SER)

Pop: 28 African–American breast cancer patients Pop: 61 cancer-free African–American individuals Pop: 56 Chinese esophageal squamous cell carcinoma patients Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 76 male and female breast cancer patients Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 266 women of European descent Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 50 high-risk Jewish individuals Pop: 11 Asian individuals Pop: 11 African–American individuals Pop: 10 Caucasian individuals Pop: 56 Chinese esophageal squamous cell carcinoma patients Pop: 88 breast/ovarian cancer patients Pop: 66 cancer-free individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Note: His/His homozygotes have 1.31-fold greater risk of breast cancer Pop: 266 women of European descent Pop: 1201 British women

[52] [34] [25] [25] [25] [35] [35] [25] [52] [48] [48] [41] [25] [25] [41] [35] [25] [27] [37] [37] [63] [30] [64] [30] [65] [22] [36] [66] [66] [66] [63] [64] [64] [30] [65] [65] [65]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

187

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

ASN ASN ASN ASN ASN

Pop: 228 British women Pop: 866 German women Pop: 453 Finnish women Pop: 1195 newborn British males Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 30 ethnically diverse individuals Pop: 50 high-risk Jewish individuals Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 386 Seattle-area breast cancer patients Pop: 50 high-risk Jewish individuals Pop: 386 Seattle-area breast cancer patients Pop: 50 Norwegian breast/ovarian cancer patients Pop: 50 high-risk Jewish individuals. Note: listed as codon 504 in reference Pop: EST assembly Pop: 50 high-risk Jewish individuals Pop: 50 high-risk Jewish individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 32 ethnically diverse individuals Pop: 32 ethnically diverse individuals Pop: 158 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 386 Seattle-area breast cancer patients Pop: 71 Seattle-area cancer-free controls Pop: 27 ethnically diverse individuals Pop: 158 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 158 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 25 ethnically diverse individuals Pop: 57 Italian breast/ovarian cancer patients Pop: 57 Italian breast/ovarian cancer patients Pop: 56 Chinese esophageal squamous cell carcinoma patients—somatic mutation Pop: 71 Seattle-area cancer-free controls Pop: 386 Seattle-area breast cancer patients Pop: blast search

[65] [65] [65] [65] [22]

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

372 372 372 372 372

0.250 0.285 0.221 0.279 N/R

A A A A A

> > > > >

BRCA2 BRCA2 BRCA2

372 372 455

0.233 0.520 N/R

A > C A > C A > G

ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT) TCA (SER) > TCG (SER)

BRCA2 BRCA2 BRCA2 BRCA2

455 455 462 484

0.001 0.010 0.001 0.010

A A A G

TCA (SER) > TCG (SER) TCA (SER) > TCG (SER) GAA (GLU) > GGA (GLY) GGA (GLY) > TGA (stop)

BRCA2

505

0.010

T > G

ATA (ILE) > AGA (ARG)

BRCA2 BRCA2 BRCA2 BRCA2

599 608 655 743

0.50 0.010 0.080 0.033

T C C T

TCT (SER) > TTT (PHE) GAC (ASP) > GAT (ASP) CCA (PRO) > CGA (ARG) CAT (HIS) > CAC (HIS)

BRCA2

743

N/R

T > C

CAT (HIS) > CAC (HIS)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

929 987 991 991 991

0.00 0.00 0.019 0.021 0.033

T A A A A

C T G G G

TTA (LEU) > TCA (SER) AAT (ASN) > ATT (ILE) AAC (ASN) > GAC (ASP) AAC (ASN) > GAC (ASP) AAC (ASN) > GAC (ASP)

BRCA2

991

N/R

A > G

AAC (ASN) > GAC (ASP)

BRCA2

1019

0.008

C > G

CTC (LEU) > GTC (VAL)

BRCA2

1132

0.092

A > G

AAA (LYS) > AAG (LYS)

BRCA2

1132

N/R

A > G

AAA (LYS) > AAG (LYS)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

1132 1132 1132 1147 1147 1172 1172 1172

0.040 0.063 0.17 0.152 0.191 0.006 0.021 0.017

A A A A A G G G

G G G G G A A A

AAA (LYS) > AAG (LYS) AAA (LYS) > AAG (LYS) AAA (LYS) > AAG (LYS) AAC (ASN) > AGC (SER) AAC (ASN) > AGC (SER) TCG (SER) > TCA (SER) TCG (SER) > TCA (SER) TCG (SER) > TCA (SER)

BRCA2

1269

0.100

T > C

GTT (VAL) > GTC (VAL)

BRCA2

1269

N/R

T > C

GTT (VAL) > GTC (VAL)

BRCA2 BRCA2 BRCA2 BRCA2

1269 1305 1334 1338

0.340 N/R 0.009 0.009

T T T C

C C A T

GTT (VAL) > GTC (VAL) TTT (PHE) > TCT (SER) TTA (LEU) > TAA (stop) GGC (GLY) > GGT (GLY)

BRCA2 BRCA2 BRCA2

1363 1521 1561

0.007 0.001 N/R

C > T A > G C > A

AAC (ASN) > AAT (ASN) CTG (LEU) > CTA (LEU) CAT (HIS) > AAT (HIS)

> > > >

> > > >

> > > > >

> > > > > > > >

> > > >

C C C C C

G G G T

C T G C

(AAT) (AAT) (AAT) (AAT) (AAT)

> > > > >

HIS HIS HIS HIS HIS

(CTT) (CTT) (CTT) (CTT) (CTT)

[57] [36] [22] [67] [36] [67] [32] [36] [61] [36] [36] [30] [22] [57] [57] [64] [64] [30] [22] [30] [30] [22] [67] [67] [57] [64] [64] [64] [64] [30] [30] [22] [57] [68] [68] [63] [67] [67] [66]

188

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA2 BRCA2

1610 1682

0.001 0.009

G > A T > C

GTG (VAL) > GTA (VAL) AGT (SER) > AGC (SER)

[67] [63]

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

1809 1882 1882 1894 1915 1915 1915

0.001 0.006 0.036 0.036 0.057 0.043 0.008

C C C C C C C

T A A G T T T

TGC (CYS) > TGT (CYS) TCA (SER) > TAA (stop) TCA (SER) > stop TAC (TYR) > TAG (stop) ACG (THR) > ATG (MET) ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

BRCA2 BRCA2

1915 1970

0.053 0.004

C > T C > A

ACG (THR) > ATG (MET) TCA (SER) > TAA (stop)

BRCA2

1988

0.009

G > A

GTA (VAL) > ATA (ILE)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

2034 2034 2034 2057 2171 2171 2171 2282

0.019 0.011 0.007 0.009 0.05 0.00 0.00 0.03

C C C G C C C A

CGT (ARG) > TGT (CYS) CGT (ARG) > TGT (CYS) CGT (ARG) > TGT (CYS) GGA (GLY) > TGA (stop) GTC (VAL) > GTG (VAL) GTC (VAL) > GTG (VAL) GTC (VAL) > GTG (VAL) GAA (GLU) > GAG (GLU)

BRCA2

2339

0.018

G > T/C

AAG (LYS) > AA (T/C) (ASN)

BRCA2

2339

0.000

G > T/C

AAG (LYS) > AA (T/C) (ASN)

BRCA2

2384

0.000

C > A

CAA (GLN) > AAA (LYS)

BRCA2

2384

0.018

C > A

CAA (GLN) > AAA (LYS)

BRCA2 BRCA2 BRCA2

2414 2414 2414

0.167 0.181 0.008

A > G A > G A > G

TCA (SER) > TCG (SER) TCA (SER) > TCG (SER) TCA (SER) > TCG (SER)

BRCA2

2414

N/R

A > G

TCA (SER) > TCG (SER)

BRCA2 BRCA2

2414 2421

0.007 0.008

A > G C > T

TCA (SER) > TCG (SER) CAG (GLN) > TAG (stop)

BRCA2

2440

0.018

C > G

CAT (HIS) > CGT (ARG)

BRCA2

2440

0.015

C > G

CAT (HIS) > CGT (ARG)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

2494 2494 2689 2811 2834 2842

0.009 0 0.006 0.001 0.001 0.009

G G T A T C

> > > > > >

A A A G C T

CGA (ARG) > CAA (GLN) CGA (ARG) > CAA (GLN) TGT (CYS) > TGA (stop) GAT (ASP) > GGT (GLY) TCA (SER) > CCA (PRO) CGC (ARG) > TGC (CYS)

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

2858 2951 2960 2988 3013 3019

0.009 N/R 0.009 0.009 0.001 0.006

C G C A C A

> > > > > >

T A T G T G

CAA (GLN) > TAA (stop) GCC (ALA) > ACC (THR) CAA (GLN) > TAA (stop) AGT (SER) > GGT (GLY) ACT (THR) > ATT (ILE) AAA (LYS) > AAG (LYS)

Pop: 386 Seattle-area breast cancer patients Pop: 56 Chinese esophageal squamous cell carcinoma patients—somatic mutation Pop: 386 Seattle-area breast cancer patients Pop: 81 Dutch breast/ovarian cancer families Pop: 14 breast cancer families Pop: 14 breast cancer families Pop: 158 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 266 women of European descent Pop: 112 British breast/ovarian cancer families Pop: 56 Chinese esophageal squamous cell carcinoma patients—somatic mutation Pop: 158 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 266 women of European descent Pop: 57 Italian breast/ovarian cancer patients Pop: 19 Asian individuals Pop: 18 African–American individuals Pop: 20 Caucasian individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 28 African–American breast cancer patients Pop: 61 cancer-free African–American individuals Pop: 61 cancer-free African–American individuals Pop: 28 African–American breast cancer patients Pop: 156 breast/ovarian cancer patients Pop: 94 cancer-free individuals Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 71 Seattle-area cancer-free controls Pop: 30 Caucasian breast/ovarian cancer patients and 30 cancer-free controls Pop: 28 African–American breast cancer patients Pop: 61 cancer-free African–American individuals Pop: 57 Italian breast/ovarian cancer patients Pop: 90 cancer-free Italian individuals Pop: 81 Dutch breast/ovarian cancer families Pop: 386 Seattle-area breast cancer patients Pop: 386 Seattle-area breast cancer patients Pop: 56 Chinese esophageal squamous cell carcinoma patients—somatic mutation Pop: 57 Italian breast/ovarian cancer patients Pop: 57 Italian breast/ovarian cancer patients Pop: 57 Italian breast/ovarian cancer patients Pop: 57 Italian breast/ovarian cancer patients Pop: 386 Seattle-area breast cancer patients Pop: 158 breast/ovarian cancer patients

> > > > > > >

> > > > > > > >

T T T T G G G G

[67] [69] [70] [70] [64] [64] [30] [65] [35] [63] [64] [64] [65] [68] [66] [66] [66] [30] [37] [37] [37] [37] [64] [64] [30] [22] [67] [30] [37] [37] [68] [68] [69] [67] [67] [63] [68] [68] [68] [68] [67] [64]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

189

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

3019 3039 3092 3098 3205 3300

0.011 0.006 0.007 0.001 0.002 0.009

A > G G > A A > G T > C GC > CT C > T

AAA (LYS) > AAG (LYS) CCG (PRO) > CCA (PRO) TAT (TYR) > TGT (CYS) TAC (TYR) > CAC (HIS) GCT (ALA) > CTT (LEU) CCA (PRO) > TCA (SER)

[64] [69] [67] [67] [67] [63]

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

3326 3326 3326 3326 3401 3412

0.007 0.002 0.021 0.017 0.008 N/R

A A A A C A

AAA (LYS) > TAA (stop) AAA (LYS) > TAA (stop) AAA (LYS) > TAA (stop) AAA (LYS) > TAA (stop) ACG (THR) > ATG (MET) ATT (ILE) > GTT (VAL)

BRCA2

3412

0.010

A > G

ATT (ILE) > GTT (VAL)

Pop: 94 cancer-free individuals Pop: 81 Dutch breast/ovarian cancer families Pop: 71 Seattle-area cancer-free controls Pop: 386 Seattle-area breast cancer patients Pop: 386 Seattle-area breast cancer patients Pop: 56 Chinese esophageal squamous cell carcinoma patients Pop: 266 women of European descent Pop: 386 Seattle-area breast cancer patients Pop: 71 Seattle-area cancer-free controls Pop: 57 Italian breast/ovarian cancer patients Pop: 66 Polish breast/ovarian cancer families Pop: 18 Taiwanese breast cancer families and cancer-free controls Pop: 50 high-risk Jewish individuals

DMC1

199

0.104

A > G

ATG (MET) > GTG (VAL)

24 ethnically diverse individuals

[57]

G22P1 G22P1 G22P1 G22P1

593 593 593 593

0.37 0.37 0.36 0.234

G G G G

GGG GGG GGG GGG

Pop: Pop: Pop: Pop:

[45] [71] [71] [72]

hHR21 hHR21

480 480

0.147 0.158

T > C T > C

GCT (ALA) > GCC (ALA) GCT (ALA) > GCC (ALA)

hHR21

481

0.026

G > A

GGA (GLY) > AGA (ARG)

LIG3 LIG3 LIG3 LIG3

374 592 737 780

0.006 N/R 0.023 0.034

G A A G

GTG GAC CAA CGC

LIG4

? (3 in reference)

N/A

C > T

ALA > VAL

LIG4

? (9 in reference)

N/A

C > T

THR > ILE

LIG4 LIG4 LIG4 LIG4 LIG4

104 164 202 238 ? (278 in reference)

0.006 0.006 0.023 N/R N/A

T C C T G

CTT (LEU) > CTC (LEU) CCT (PRO) > TCT (SER) TAC (TYR) > TAT (TYR) TCT (SER) > TCC (SER) ARG > HIS

LIG4 LIG4

394 ? (469 in reference)

N/R N/A

A > G G > A

GAA (GLU) > GGA (GLY) GLY > GLU

LIG4 LIG4 LIG4 LIG4 LIG4 LIG4 LIG4

501 501 501 501 501 501 ? (580 in reference)

0.074 0.097 0.15 0.15 0.165 0.097 N/A

T T T T T T C

> > > > > > >

C C C C C C T

GAT (ASP) > GAT (ASP) > GAT (ASP) > GAT (ASP) > GAT (ASP) > GAT (ASP) > ARG > stop

LIG4 LIG4 LIG4 LIG4

591 593 790 ? (814 in reference)

N/R 0.006 0.023 N/A

A A G C

> > > >

G G A T

ATA (ILE) > GTA (VAL) GAG (GLU) > GAA (GLU) GCT (ALA) > ACT (THR) ARG > stop

> > > > > >

> > > >

> > > >

> > > > >

T T T T T G

T T T T

A T G A

C T T C A

(GLY) (GLY) (GLY) (GLY)

> > > >

GGT GGT GGT GGT

(GLY) (GLY) (GLY) (GLY)

(VAL) > GTA (VAL) (ASP) > GTC (VAL) (GLN) > CAG (GLN) (ARG) > CAC (HIS)

GAC GAC GAC GAC GAC GAC

(ASP) (ASP) (ASP) (ASP) (ASP) (ASP)

1094 British breast cancer patients 1440 British breast cancer patients 864 cancer-free British individuals 47 ethnically diverse individuals

[65] [67] [67] [68] [29] [22] [36]

Pop: 746 Japanese individuals Pop: 6 of 19 radiation sensitive cancer patients Pop: 1 of 19 radiation sensitive cancer patients

[53] [73]

Pop: Pop: Pop: Pop:

86 ethnically diverse individuals EST assembly 87 ethnically diverse individuals 89 ethnically diverse individuals

[74] [75] [74] [74]

Note: homozygous in a DNA Ligase 4 deficient patient Note: homozygous in a DNA Ligase 4 deficient patient Pop: 85 ethnically diverse individuals Pop: 87 ethnically diverse individuals Pop: 87 ethnically diverse individuals Pop: 984 ethnically diverse individuals Note: homozygous in a DNA Ligase 4 deficient patient Pop: 984 ethnically diverse individuals Note: heterozygous in a Lig4 deficient patient with R814X allele Pop: 88 ethnically diverse individuals Pop: 984 ethnically diverse individuals Pop: 2014 British breast cancer patients Pop: 2592 British breast cancer patients Pop: 2016 cancer-free British individuals Pop: 41 ethnically diverse individuals Note: one of two nonsense mutations in a Lig4 deficient patient Pop: 984 ethnically diverse individuals Pop: 89 ethnically diverse individuals Pop: 89 ethnically diverse individuals Note: observed in two unrelated Lig4 deficient patients

[76]

[73]

[76] [74] [74] [74] [77] [76] [77] [76] [74] [77] [45] [71] [71] [72] [76] [77] [74] [74] [76]

190

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

Pop: EST assembly Pop: 44 ethnically diverse individuals Pop: 157 primary tumor samples Note: results in ataxia-telangiectasia-like disorder Pop: 157 primary tumor samples Pop: 44 ethnically diverse individuals Pop: 157 primary tumor samples—somatic mutation Pop: 157 primary tumor samples Note: results in ataxia-telangiectasia-like disorder Pop: 44 ethnically diverse individuals Pop: 169 cancer-free individuals Note: results in nonsense-mediated mRNA decay and AT-like disorder

[61] [72] [78] [79]

[45] [71] [71] [72] [81]

MRE11A MRE11A MRE11A MRE11A

31 40 104 117

0.50 0.011 0.003 N/A

T C A A

> > > >

C T T G

GTC (VAL) > GCC (ALA) CTC (LEU) > CTT (LEU) AGT (SER) > TGT (CYS) AAC (ASN) > AGC (SER)

MRE11A MRE11A MRE11A

157 468 503

0.006 0.011 0.003

A > G A > G G > A

ATG (MET) > GTG (VAL) GAT (ASP) > GGT (GLY) CGT (ARG) > CAT (HIS)

MRE11A MRE11A

572 633

0.003 N/A

G > A C > T

CGA (ARG) > CAA (GLN) CGA (ARG) > TGA (stop)

MRE11A MRE11A MRE11A

698 N/A ntd 1714

0.011 0 N/A

A > G N/A C > T

ATG (MET) > GTG (VAL) N/A ntd 1714 CTG CTG CTG CTG TCG

> > > > >

0.34 0.34 0.33 0.345 0.011

G G G G C

NBS1

95

0.011

G > A

GAT (ASP) > AAT (ASN)

NBS1 NBS1

142 171

0.005 0.043

A > G A > G

AAT (ASN) > AGT (SER) ATT (ILE) > GTT (VAL)

NBS1 NBS1 NBS1 NBS1 NBS1 NBS1

185 185 185 185 185 215

0.35 0.504 0.345 0.32 0.333 0.011

G G G G G C

> > > > > >

C C C C C T

GAG GAG GAG GAG GAG CGG

NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1 NBS1

216 266 399 399 399 399 497 672 672 672 672 672

0.006 0.029 0.39 0.38 0.38 0.50 N/R 0.35 0.34 0.33 0.333 0.333

C C T T T T A A A A A A

> > > > > > > > > > > >

A T C C C C G G G G G G

CAG (GLN) > AAG (LYS) CCG (PRO) > CTG (LEU) GAT (ASP) > GAC (ASP) GAT (ASP) > GAC (ASP) GAT (ASP) > GAC (ASP) GAT (ASP) > GAC (ASP) ACA (THR) > GCA (ALA) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO)

Pop: 1467 British breast cancer patients Pop: 1920 British breast cancer patients Pop: 864 cancer-free British individuals 87 ethnically diverse individuals Pop: 47 German acute lymphoblastic leukemia patients Pop: somatic mutation in 1 of 47 acute lymphoblastic leukemia patients Pop: 93 ethnically diverse individuals Pop: 47 German acute lymphoblastic leukemia patients Pop: 1558 British breast cancer patients Pop: 745 Japanese individuals Pop: 2016 British breast cancer patients Pop: 864 cancer-free British individuals Pop: 87 ethnically diverse individuals Pop: 47 German acute lymphoblastic leukemia patients Pop: 78 ethnically diverse individuals Pop: 85 ethnically diverse individuals Pop: 1576 British breast cancer patients Pop: 2016 British breast cancer patients Pop: 864 cancer-free British individuals Pop: 84 ethnically diverse individuals Pop: microarray screening of 37 individuals Pop: 1593 British breast cancer patients Pop: 2016 British breast cancer patients Pop: 864 cancer-free British individuals Pop: 90 ethnically diverse individuals Pop: 90 ethnically diverse individuals

PRKDC

N/A

0.000

N/A

N/A

No SNPs reported

RAD50

191

<0.05

?

Pop: 72 ethnically diverse individuals

[71]

RAD50 RAD50 RAD50 RAD50 RAD50 RAD50 RAD50 RAD50 RAD50

616 697 826 884 964 1038 1139 1239 1282

0.43 0.33 <0.05 <0.05 0.50 0.50 0.38 <0.05 N/R

A T C G T A A G T

ACA (THR) > ? (Thr > Leu in reference) AAA (LYS) > GAA (GLU) GTC (VAL) > GCC (ALA) CAA (GLN) > TAA (stop) CGT (ARG) > CAT (HIS) TAT (TYR) > CAT (HIS) AGA (ARG) > GGA (GLY) AAA (LYS) > AAG (LYS) CGA (ARG) > CAA (GLN) TAT (TYR) > TAC (TYR)

Pop: Pop: Pop: Pop: Pop: Pop: Pop: Pop: Pop:

[61] [61] [71] [71] [61] [61] [61] [71] [75]

(GLU) (GLU) (GLU) (GLU) (GLU) (ARG)

> > > > >

> > > > > >

CTA CTA CTA CTA TTG

(LEU) (LEU) (LEU) (LEU) (LEU)

[72] [78] [80]

34 34 34 34 93

G C T A C G G A C

(LEU) (LEU) (LEU) (LEU) (SER)

[78] [79]

NBS1 NBS1 NBS1 NBS1 NBS1

> > > > > > > > >

A A A A T

[78] [72] [78]

CAG CAG CAG CAG CAG TGG

(GLN) (GLN) (GLN) (GLN) (GLN) (TRP)

EST assembly EST assembly 72 ethnically diverse individuals 72 ethnically diverse individuals EST assembly EST assembly EST assembly 72 ethnically diverse individuals EST assembly

[81] [72] [81] [45] [53] [71] [71] [72] [81] [72] [72] [45] [71] [71] [72] [82] [45] [71] [71] [72] [72]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

191

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

Pop: 45 Japanese breast cancer patients from high-risk families Pop: 200 Japanese sporadic breast cancer patients Pop: 100 Japanese colon cancer patients Pop: EST assembly Pop: EST assembly Pop: 100 Boston-area early-onset breast cancer patients Pop: 127 cancer-free controls of western European descent

[83]

–a

RAD51

150

0.022

G > A

GGC (ARG) > GAC (GLN)

RAD51

150

0

G > A

GGC (ARG) > GAC (GLN)

RAD51 RAD51 RAD51 RAD51

150 226 313 N/A

0 N/R 0.48 0.000

G > A C > T A > C N/A

GGC (ARG) > GAC (GLN) GCC (ALA) > GCT (ALA) AAA (LYS) > CAA (GLN) N/A

RAD51

N/A

0.000

N/A

N/A

RAD51C

N/A

0.000

N/A

N/A

Pop: 100 cancer-free controls of western European descent

RAD51L1

N/A

0.000

N/A

N/A

No SNPs reported

RAD51L3

N/A

0.000

N/A

N/A

No SNPs reported

RAD52

346

0.030

C > A

TCG (SER) > TAG (stop)

[84]

RAD52

415

0.020

T > G

TAT (TYR) > TAG (stop)

RAD52

N/A

0.000

N/A

N/A

Pop: 100 Boston-area early-onset breast cancer patients Pop: 100 Boston-area early-onset breast cancer patients No SNPs reported

RAD54

63

0.004

C > A

CCT (PRO) > CAT (HIS)

[86]

RAD54 RAD54

63 151

0.000 0.02

C > A A > G

CCT (PRO) > CAT (HIS) AAG (LYS) > GAG (GLU)

RAD54

325

0.008

G > A

GGA (GLY) > AGA (ARG)

RAD54 RAD54

325 366

0.000 0.08

G > A C > T

GGA (GLY) > AGA (ARG) GAC (ASP) > GAT (ASP)

RAD54

433

0.02

G > A

CCG (PRO) > CCA (PRO)

RAD54

444

0.004

T > A

GTG (VAL) > GAG (GLU)

RAD54 RAD54

444 657

0.000 0.010

T > A C > G

RAD54

730

0.19

C > T

GTG (VAL) > GAG (GLU) Unknown (Cys > Ser in reference) GCC (ALA) > GCT (ALA)

Pop: 132 primary lymphomas, breast and colorectal tumors from Japanese patients Pop: 100 cancer-free Japanese individuals Pop: 132 primary tumors and 100 cancer-free Japanese individuals Pop: 132 primary lymphomas, breast and colorectal tumors from Japanese patients Pop: 100 cancer-free Japanese individuals Pop: 132 primary tumors and 100 cancer-free Japanese individuals Pop: 132 primary tumors and 100 cancer-free Japanese individuals Pop: 132 primary lymphomas, breast and colorectal tumors from Japanese patients Pop: 100 cancer-free Japanese individuals Pop: 100 Boston-area early-onset breast cancer patients Pop: 132 primary tumors and 100 cancer-free Japanese individuals

RAD54B RAD54B

97 250

N/R 0.609

G > C T > C

GAT (ASP) > CAT (HIS) AAT (ASN) > AAC (ASN)

[87] [88]

RAD54B RAD54B

250 396

N/R 0.063

T > C A > G

AAT (ASN) > AAC (ASN) GAA (GLU) > GAG (GLU)

RAD54B

418

0.022

A > G

AAT (ASN) > AGT (SER)

RAD54B

593

0.022

G > T

GAT (ASP) > TAT (TYR)

Pop: clone assembly Pop: 23 primary lymphomas and colorectal cancer from Japanese patients Pop: EST assembly Pop: 24 primary lymphomas and colorectal cancer from Japanese patients Note: homozygous mutation in primary colon tumor from Japanese patient Note: homozygous mutation in primary lymphoma from Japanese patient

RAD54L

N/A

0.000

N/A

N/A

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

7 10 42 50 51 56

0.003 0.001 0.014 0.003 0.021 0.001

G G C G A C

> > > > > >

T A A A T T

CGC GTG ACC GAG AAG CAC

[83] [83] [75] [61] [84] [85]

[84]

[86] [86] [86] [86] [86] [86] [86] [86] [84] [86]

[53] [88] [88] [88]

No SNPs reported (ARG) > CTC (LEU) (VAL) > ATG (MET) (THR) > ACA (THR) (GLU) > GAA (GLU) (LYS) > TAG (stop) (HIS) > CAT (HIS)

Pop: Pop: Pop: Pop: Pop: Pop:

398 ethnically diverse individuals 397 ethnically diverse individuals 424 ethnically diverse individuals 436 ethnically diverse individuals survey of 94 human STS 436 ethnically diverse individuals

[72] [72] [72] [72] [89] [72]

192

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Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

72 157 158 161 190 194 194 194 194 194

0.020 0.001 0.001 0.004 0.004 0.10 0.126 0.115 0.051 0.045

T G A C C C C C C C

C A T T G T T T T T

GTG (VAL) > GCG (ALA) GAG (GLU) > AAG (LYS) GCA (ALA) > GCT (ALA) CCG (PRO) > CTG (LEU) CTC (LEU) > CTG (LEU) CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP)

[72] [72] [72] [72] [72] [50] [72] [90] [90] [91]

XRCC1

194

0.082

C > T

CGG (ARG) > TGG (TRP)

XRCC1 XRCC1 XRCC1 XRCC1

194 194 194 194

0.061 0.059 0.341 0.341

C C C C

> > > >

T T T T

CGG CGG CGG CGG

(ARG) (ARG) (ARG) (ARG)

> > > >

TGG TGG TGG TGG

(TRP) (TRP) (TRP) (TRP)

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

194 194 194 194 194 194 194 194 194 194

0.06 0.05 0.27 0.082 0.081 0.346 0.285 0.25 0.07 N/A

C C C C C C C C C C

> > > > > > > > > >

T T T T T T T T T T

CGG CGG CGG CGG CGG CGG CGG CGG CGG CGG

(ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG)

> > > > > > > > > >

TGG TGG TGG TGG TGG TGG TGG TGG TGG TGG

(TRP) (TRP) (TRP) (TRP) (TRP) (TRP) (TRP) (TRP) (TRP) (TRP)

XRCC1 XRCC1

194 194

0.050 0.07

C > T C > T

CGG (ARG) > TGG (TRP) CGG (ARG) > TGG (TRP)

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

194 199 206 206 206 280 280 280 280

0.09 0.001 0.26 0.671 0.42 0.070 0.074 0.075 N/A

C C A A A G G G G

> > > > > > > > >

T T G G G A A A A

CGG (ARG) > TGG (TRP) TCC (SER) > TCT (SER) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO) CCA (PRO) > CCG (PRO) CGT (ARG) > CAT (HIS) CGT (ARG) > CAT (HIS) CGT (ARG) > CAT (HIS) CGT (ARG) > CAT (HIS)

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

298 304 309 309 326 381 399 399 399

0.004 0.032 0.004 0.021 0.002 N/R 0.32 N/A 0.216

A A C C G G G G G

> > > > > > > > >

C G T T T A A A A

AAA (LYS) > AAC (ASN) ACC (THR) > GCC (ALA) CCC (PRO) > TCC (SER) CCC (PRO) > TCC (SER) GTG (VAL) > GTT (VAL) GTG (VAL) > ATG (MET) CGG (ARG) > CAG (GLN) CGG (ARG) > CAG (GLN) CGG (ARG) > CAG (GLN)

XRCC1

399

N/A

G > A

CGG (ARG) > CAG (GLN)

XRCC1 XRCC1 XRCC1 XRCC1

399 399 399 399

N/A 0.34 0.34 0.39

G G G G

CGG CGG CGG CGG

Pop: 433 ethnically diverse individuals Pop: 408 ethnically diverse individuals Pop: 407 ethnically diverse individuals Pop: 408 ethnically diverse individuals Pop: 407 ethnically diverse individuals Pop: 25 ethnically diverse individuals Pop: 441 ethnically diverse individuals Pop: 48 Egyptian colorectal cancer patients Pop: 48 Egyptian cancer-free controls Pop: 154 African–American lung cancer patients Pop: 243 cancer-free African–American controls Pop: 180 Caucasian lung cancer patients Pop: 461 cancer-free Caucasian controls Pop: 205 Korean breast cancer patients Pop: 205 female Korean cancer-free individuals Pop: 169 North Carolina Caucasians Pop: 98 North Carolina African–Americans Pop: 120 Taiwanese maternity subjects Pop: 98 Caucasian head/neck cancer patients Pop: 161 Caucasian cancer-free individuals Pop: 166 cancer-free Chinese individuals Pop: 188 Chinese gastric cancer patients Pop: 12 cancer-free individuals Pop: 424 cancer-free individuals Note: Lack of T allele increased SCC risk (OR = 2.46) Pop: 80 cancer-free Caucasian individuals Pop: 125 British Caucasian melanoma patients Pop: 211 British Caucasian individuals Pop: 406 ethnically diverse individuals Pop: 25 ethnically diverse individuals Pop: 441 ethnically diverse individuals Pop: 12 cancer-free individuals Pop: 409 ethnically diverse individuals Pop: survey of 94 human STS Pop: 80 cancer-free Caucasian individuals Note: SNP associated with increased frequency of bleomycin-induced chromosomal breaks Pop: 413 ethnically diverse individuals Pop: survey of 97 human STS Pop: 415 ethnically diverse individuals Pop: survey of 94 human STS Pop: 422 ethnically diverse individuals Pop: 24 Japanese individuals Pop: 143 cancer-free Caucasians Note: Gln/Gln associated with increase risk. Pop: 67 samples from lung cancer patients and controls. Note: Gln/Gln associated with increased DNA damage. Note: Gln allele associated with IR sensitivity Pop: 308 Italian individuals Pop: 124 Italian bladder cancer patients Pop: 85 Italian cancer-free hospital patients

> > > > > > > > > >

> > > >

A A A A

(ARG) (ARG) (ARG) (ARG)

> > > >

CAG CAG CAG CAG

(GLN) (GLN) (GLN) (GLN)

[91] [91] [91] [92] [92] [93] [93] [93] [94] [94] [95] [95] [96] [97] [97] [98] [99] [99] [72] [57] [72] [96] [72] [89] [98] [98]

[72] [89] [72] [89] [72] [53] [100] [100] [101] [101] [102] [103] [103] [103]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

193

Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

XRCC1 XRCC1 XRCC1 XRCC1

399 399 399 399

0.284 0.222 0.392 0.642

G G G G

> > > >

A A A A

CGG CGG CGG CGG

(ARG) (ARG) (ARG) (ARG)

> > > >

CAG CAG CAG CAG

(GLN) (GLN) (GLN) (GLN)

[104] [104] [105] [105]

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

399 399 399 399 399

0.267 0.33 0.320 0.133 0.169

G G G G G

> > > > >

A A A A A

CGG CGG CGG CGG CGG

(ARG) (ARG) (ARG) (ARG) (ARG)

> > > > >

CAG CAG CAG CAG CAG

(GLN) (GLN) (GLN) (GLN) (GLN)

XRCC1

399

0.181

G > A

CGG (ARG) > CAG (GLN)

XRCC1 XRCC1 XRCC1 XRCC1

399 399 399 399

0.306 0.361 0.358 0.315

G G G G

CGG CGG CGG CGG

XRCC1

399

N/A

G > A

CGG (ARG) > CAG (GLN)

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

399 399 399 399 399 399 399 399

0.286 0.360 0.256 0.290 0.25 0.34 0.344 0.39

G G G G G G G G

> > > > > > > >

A A A A A A A A

CGG CGG CGG CGG CGG CGG CGG CGG

XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

399 407 418 485 514 559 560 562 571 576 632 632

0.36 0.001 N/R 0.002 0.011 0.001 0.001 0.001 0.001 N/R 0.292 0.42

G T C C C G C C G A G G

> > > > > > > > > > > >

A A T A T A T G A T A A

CGG (ARG) > CAG (GLN) GGT (GLY) > GGA (GLY) AGC (SER) > AGT (SER) TCT (SER) > TAT (TYR) CCT (PRO) > CTG (LEU) CGG (ARG) > CAG (GLN) CGG (ARG) > TGG (TRP) CTC (LEU) > CTG (LEU) AGG (ARG) > AGA (ARG) AAT (ASN) > TAT (TYR) CAG (GLN) > CAA (GLN) CAG (GLN) > CAA (GLN)

Pop: 192 male Korean lung cancer patients Pop: 135 cancer-free Korean men Pop: 175 British newborns Pop: 14 British newborns with extreme glycophorin A NN-variant frequencies Pop: 422 ethnically diverse individuals Pop: survey of 94 human STS Pop: 48 Egyptian colorectal cancer patients Pop: 48 Egyptian cancer-free controls Pop: 154 African–American lung cancer patients Pop: 243 cancer-free African–American controls Pop: 180 Caucasian lung cancer patients Pop: 461 cancer-free Caucasian controls Pop: 205 Korean breast cancer patients Pop: 205 female Korean cancer-free individuals Note: Gln alleles associated with decreased repair efficiency Pop: 98 Caucasian head/neck cancer patients Pop: 161 Caucasian cancer-free individuals Pop: 166 cancer-free Chinese individuals Pop: 188 Chinese gastric cancer patients Pop: 12 cancer-free individuals Pop: 424 cancer-free individuals Pop: 80 cancer-free Caucasian individuals Pop: 125 British Caucasian melanoma patients Pop: 211 British Caucasian individuals Pop: 426 ethnically diverse individuals Pop: 24 Japanese individuals Pop: 410 ethnically diverse individuals Pop: survey of 94 human STS Pop: 416 ethnically diverse individuals Pop: 416 ethnically diverse individuals Pop: 416 ethnically diverse individuals Pop: 414 ethnically diverse individuals Pop: clone assembly Pop: 420 ethnically diverse individuals Pop: 12 cancer-free individuals

XRCC2

188

0.091

G > A

CGC (ARG) > CAC (HIS)

XRCC2

188

0.071

G > A

CGC (ARG) > CAC (HIS)

XRCC2 XRCC2

188 188

0.075 0.075

G > A G > A

CGC (ARG) > CAC (HIS) CGC (ARG) > CAC (HIS)

XRCC3 XRCC3 XRCC3

241 241 241

N/R 0.42 N/A

C > T C > T C > T

ACG (THR) > ATG (MET) ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

XRCC3 XRCC3 XRCC3

241 241 241

0.48 0.35 N/A

C > T C > T C > T

ACG (THR) > ATG (MET) ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

XRCC3 XRCC3 XRCC3

241 241 241

0.395 0.36 0.43

C > T C > T C > T

ACG (THR) > ATG (MET) ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

> > > >

A A A A

(ARG) (ARG) (ARG) (ARG)

(ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG) (ARG)

> > > >

> > > > > > > >

CAG CAG CAG CAG

CAG CAG CAG CAG CAG CAG CAG CAG

(GLN) (GLN) (GLN) (GLN)

(GLN) (GLN) (GLN) (GLN) (GLN) (GLN) (GLN) (GLN)

Pop: 521 breast cancer patients of north European descent Pop: 895 cancer-free individuals of north European descent Pop: 2016 British breast cancer patients Pop: 2016 cancer-free British individuals Pop: 135 cancer-free women Pop: 308 Italian individuals Note: MET homozygotes had significantly higher levels of DNA adducts Pop: 124 Italian bladder cancer patients Pop: 85 Italian cancer-free hospital patients Note: SNP not associated with lung cancer risk Pop: 2304 British breast cancer patients Pop: 1920 cancer-free British individuals Pop: 12 cancer-free individuals

[72] [89] [90] [90] [91] [91] [91] [91] [92] [92] [93] [94] [94] [95] [95] [96] [97] [98] [99] [99] [72] [53] [72] [89] [72] [72] [72] [72] [87] [72] [96] [106] [106] [71] [71] [102] [103] [103] [103] [103] [107] [71] [71] [96]

194

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Table 3 (Continued ) Symbol

Amino acid number

Allele frequency

Base change

Amino acid substitution

Population

Reference

XRCC3 XRCC3

241 241

0.444 0.30

C > T C > T

ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

[98] [99]

XRCC3 XRCC3

241 241

0.38 N/A

C > T C > T

ACG (THR) > ATG (MET) ACG (THR) > ATG (MET)

Pop: 80 cancer-free Caucasians Pop: 125 British Caucasian melanoma patients Pop: 211 British Caucasians Note: T allele sig. associated with melanoma risk

XRCC4

134

0.05

T > C

ATT (ILE) > ACT (THR)

[85]

XRCC4

307

0.09

T > G

TCT (SER) > TCG (SER)

Pop: 128 European Pop: 128 European

XRCC5 XRCC5 XRCC5 XRCC5 XRCC5

335 463 508 524 524

0.03 0.011 0.003 0.076 0.167

C G A A G

TCG (SER) > TTG (LEU) TTG (LEU) > TTC (PHE) ATT (ILE) > GTT (VAL) ACA (THR) > ACG (THR) ACG (THR) > ACA (THR)

> > > > >

T C G G A

Pop: Pop: Pop: Pop: Pop:

cancer-free controls of western descent cancer-free controls of western descent

16 multiple myeloma cell lines 46 ethnically diverse individuals 735 Japanese individuals 740 Japanese individuals 43 ethnically diverse individuals

[99] [99]

[85] [108] [72] [53] [53] [72]

N/R, not reported; N/A, not applicable. a Unpublished data from our lab.

BRCA1 and BRCA2, data for some SNPs were verified using the Breast Cancer Mutation database (http://www.nhgri.nih.gov/Intramural research/ Lab transfer/Bic/). PubMed was searched to identify papers reporting variants in any of these genes. For variants in which multiple reports were available from different sources, only those sources reporting population data were entered in the table. Codon information, if not provided, was determined from NCBI reference sequences. Allele frequencies were calculated from the genotype data reported in the given reference.

3. Results and discussion DNA strand breaks result from both radiation and radiomimetic chemical exposures as well as from normal cellular activity. Since variation in several DSBR genes is known to affect disease predisposition, research to identify additional variants has been enticing. Twenty-four DSBR genes were selected for inclusion in this compilation (Table 1). Table 2 summarizes the total number of DSBR SNPs reported in the literature and public databases, including two novel SNPs identified in our laboratory. Table 3 expands upon these SNPs, providing codon sequences, population information and allele frequencies. In or-

der to more readily identify common1 SNPs, data from “healthy” (cancer-free at time of sampling) populations were pooled and the average allele frequency at each position was determined (Table 4). From all populations included in this report, 299 distinct cSNPs were reported at an average frequency of approximately once per every 235 base pairs (0.0042 SNPs per bp). In order to remove bias introduced from screening high-risk populations, only healthy population data were used to calculate common allele frequencies. The 64 common variants were calculated to occur approximately once every 1000 base pairs (0.0009 SNPs per bp). To date, no common variants have been reported for 9 of the 24 genes. However, population data has been supplied for only three of the nine genes showing no variation: RAD51, RAD51C and RAD54. Undoubtedly, additional variants will be identified as more studies are reported. The level of variation in DNA repair genes indicates a high likelihood that few individuals will share the exact same complement of repair gene alleles. In fact, Ford et al. [85] found that only 1 of 88 subjects carried the reference sequence at all coding positions in five DNA repair genes. Four of the 88 individuals carried the most common combination of variants in the five genes. The increasing evidence that some 1 We have chosen to define “common” as an allele frequency of >1%, or 1 allele in 50 individuals.

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

195

Table 4 Summary of position and allele frequency of common SNPs (<1% allele frequency) reported in disease-free populations Symbol

Amino acid number

Allele frequency

Amino acid substitution

Population (n)

BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA1 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 BRCA2 DMC1 G22P1 hHR21 LIG3 LIG3 LIG4 LIG4 LIG4 MRE11A MRE11A MRE11A NBS1 NBS1 NBS1 NBS1 NBS1 RAD50 RAD50 RAD50 RAD50 XRCC1 XRCC1 XRCC1 XRCC1 XRCC1

38 197 356 693 694 771 871 1038 1040 1041 1183 1436 1613 1652 289 372 991 1132 1147 1172 1269 1915 2034 2171 2414 2440 3019 3326 199 593 480 737 780 202 501 790 40 468 698 34 185 266 399 672 191 826 884 1239 42 51 72 194 206

0.01 0.021 0.082 0.038 0.231 0.34 0.319 0.266 0.037 0.02 0.316 0.327 0.310 0.02 0.031 0.269 0.021 0.092 0.191 0.021 0.340 0.050 0.011 0.05 0.181 0.015 0.011 0.021 0.104 0.353 0.147 0.023 0.034 0.023 0.140 0.023 0.011 0.011 0.011 0.331 0.401 0.029 0.391 0.331 <0.05 <0.05 <0.05 <0.05 0.014 0.021 0.020 0.123 0.643

AAG (LYS) > AAA (LYS) TGC (CYS) > TGT (CYS) CAG (GLN) > CGG (ARG) GAC (ASP) > AAC (ASN) AGC (SER) > AGT (SER) TTG (LEU) > CTG (LEU) CCG (PRO) > CTG (LEU) GAA (GLU) > GGA (GLY) AGC (SER) > AAC (ASN) AGT (SER) > GGT (GLY) AAA (LYS) > AGA (ARG) TCT (SER) > TCC (SER) AGT (SER) > GGT (GLY) ATG (MET) > ATA (ILE) ASN (AAT) > HIS (CTT) ASN (AAT) > HIS (CTT) AAC (ASN) > GAC (ASP) AAA (LYS) > AAG (LYS) AAC (ASN) > AGC (SER) TCG (SER) > TCA (SER) GTT (VAL) > GTC (VAL) ACG (THR) > ATG (MET) CGT (ARG) > TGT (CYS) GTC (VAL) > GTG (VAL) TCA (SER) > TCG (SER) CAT (HIS) > CGT (ARG) AAA (LYS) > AAG (LYS) AAA (LYS) > TAA (stop) ATG (MET) > GTG (VAL) GGG (GLY) > GGT (GLY) GCT (ALA) > GCC (ALA) CAA (GLN) > CAG (GLN) CGC (ARG) > CAC (HIS) TAC (TYR) > TAT (TYR) GAT (ASP) > GAC (ASP) GCT (ALA) > ACT (THR) CTC (LEU) > CTT (LEU) GAT (ASP) > GGT (GLY) ATG (MET) > GTG (VAL) CTG (LEU) > CTA (LEU) GAG (GLU) > CAG (GLN) CCG (PRO) > CTG (LEU) GAT (ASP) > GAC (ASP) CCA (PRO) > CCG (PRO) ACA (THR) > LEU CAA (GLN) > TAA (stop) CGT (ARG) > CAT (HIS) CGA (ARG) > CAA (GLN) ACC (THR) > ACA (THR) AAG (LYS) > TAG (stop) GTG (VAL) > GCG (ALA) CGG (ARG) > TGG (TRP) CCA (PRO) > CCG (PRO)

90 94 1162 78 176 844 793 196 82 31 436 438 449 32 287 4305 94 98 94 94 25 360 94 19 94 61 94 71 24 911 746 87 89 87 3129 89 44 44 44 951 1696 85 948 1044 72 72 72 72 424 94 433 2864 478

196

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Table 4 (Continued ) Symbol XRCC1 XRCC1 XRCC1 XRCC1 XRCC1 XRCC2 XRCC3 XRCC4 XRCC4 XRCC5 XRCC5

Amino acid number 280 304 309 514 632 188 241 134 307 463 524

Allele frequency 0.071 0.032 0.021 0.011 0.296 0.074 0.371 0.05 0.09 0.011 0.081

common variants reduce DNA repair efficiency (e.g. XRCC1 194C, 399A) provides compelling support for the role of DNA repair genes in determining individual susceptibility to disease.

Acknowledgements This work was funded by grants to BWG from the Canadian Space Agency and from the Vancouver Island Breast Cancer Initiative. References [1] A. Ronen, B.W. Glickman, Human DNA repair genes, Environ. Mol. Mutagen. 37 (2001) 241–283. [2] R.D. Wood, M. Mitchell, J. Sgouros, T. Lindahl, Human DNA repair genes, Science 291 (2001) 1284–1289. [3] S.P. Jackson, Sensing and repairing DNA double-strand breaks, Carcinogenesis 23 (2002) 687–696. [4] P. Karran, DNA double strand break repair in mammalian cells, Curr. Opin. Genet. Dev. 10 (2000) 144–150. [5] A. Pastink, J.C. Eeken, P.H. Lohman, Genomic integrity and the repair of double-strand DNA breaks, Mutat. Res. 480–481 (2001) 37–50. [6] P.A. Jeggo, Identification of genes involved in repair of DNA double-strand breaks in mammalian cells, Radiat. Res. 150 (1998) S80–S91. [7] B. Elliott, M. Jasin, Double-strand breaks and translocations in cancer, Cell Mol. Life Sci. 59 (2002) 373–385. [8] J.M. Ford, P.C. Hanawalt, Role of DNA excision repair gene defects in the etiology of cancer, Curr. Top. Microbiol. Immunol. 221 (1997) 47–70. [9] H.W. Mohrenweiser, I.M. Jones, Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation, Mutat. Res. 400 (1998) 15–24.

Amino acid substitution

Population (n)

CGT (ARG) > CAT (HIS) ACC (THR) > GCC (ALA) CCC (PRO) > TCC (SER) CCT (PRO) > CTG (LEU) CAG (GLN) > CAA (GLN) CGC (ARG) > CAC (HIS) ACG (THR) > ATG (MET) ATT (ILE) > ACT (THR) TCT (SER) > TCG (SER) TTG (LEU) > TTC (PHE) ACA (THR) > ACG (THR)

583 97 94 94 432 2911 2616 128 128 46 783

[10] A. Muller, R. Fishel, Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC), Cancer Invest. 20 (2002) 102–109. [11] J. Jiricny, M. Nystrom-Lahti, Mismatch repair defects in cancer, Curr. Opin. Genet. Dev. 10 (2000) 157–161. [12] M. Berneburg, A.R. Lehmann, Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription, Adv. Genet. 43 (2001) 71–102. [13] H. vanSteeg, K.H. Kraemer, Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer, Mol. Med. Today 5 (1999) 86–94. [14] M. Cargill, D. Altshuler, J. Ireland, P. Sklar, K. Ardlie, N. Patil, N. Shaw, C.R. Lane, E.P. Lim, N. Kalyanaraman, J. Nemesh, L. Ziaugra, L. Friedland, A. Rolfe, J. Warrington, R. Lipshutz, G.Q. Daley, E.S. Lander, Characterization of single-nucleotide polymorphisms in coding regions of human genes, Nat. Genet. 22 (1999) 231–238. [15] J. McWhir, J. Selfridge, D.J. Harrison, S. Squires, D.W. Melton, Mice with DNA-repair gene (ERCC-1) deficiency have elevated levels of p53, liver abnormalities and die before weening, Nat. Genet. 5 (1993) 217–224. [16] J.J. Yu, K.B. Lee, C. Mu, Q. Li, T.V. Abernathy, F. Bostick-Bruton, E. Reed, Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene, Int. J. Oncol. 16 (2000) 555–560. [17] H. Morino, T. Kawarai, Y. Izumi, T. Kazuta, M. Oda, O. Komure, F. Udaka, M. Kameyama, S. Nakamura, H. Kawakami, A single nucleotide polymorphism of dopamine transporter gene is associated with Parkinson’s disease, Ann. Neurol. 47 (2000) 528–531. [18] P.M. Stanford, G.M. Halliday, W.S. Brooks, J.B. Kwok, C.E. Storey, H. Creasey, J.G. Morris, M.J. Fulham, P.R. Schofield, Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations, Brain 123 (2000) 880–893. [19] F.J. Couch, M.L. De Shano, M.A. Blackwood, K. Calzone, J. Stopfer, L. Campeau, A. Ganguly, T. Rebbeck, B.L. Weber, BRCA1 mutations in women attending clinics that evaluate

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200

[20]

[21]

[22]

[23] [24] [25]

[26]

[27]

[28]

[29]

the risk of breast cancer, N. Engl. J. Med. 336 (1997) 1409– 1415. K.E. Malone, J.R. Daling, J.D. Thompson, C.A. O’Brien, L.V. Francisco, E.A. Ostrander, BRCA1 mutations and breast cancer in the general population—analyses in women before age 35 years and in women before age 45 with first-degree family history, J. Am. Med. Assoc. 279 (1998) 922–929. G.H. Ho, B.H. Phang, I.S.L. Ng, H.Y. Law, K.C. Soo, E.H. Ng, Novel germline BRCA1 mutations detected in women in Singapore who developed breast carcinoma before the age of 36 years, Cancer 89 (2000) 811–816. S.S.-L. Li, H.-M. Tseng, T.-P. Yang, C.-H. Liu, S.-J. Teng, H.-W. Huang, L.-M. Chen, H.-W. Kao, J.H. Chen, J.-N. Tseng, A. Chen, M.-F. Hou, T.-J. Huang, H.-T. Chang, K.T. Mok, J.-H. Tsai, Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan, Hum. Genet. 104 (1999) 201– 204. NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP). Human Genic Bi-Allelic SEquences (HGBASE) (http:// hgbase.interactiva.de/). D. Shattuck-Eidens, A. Oliphant, M. McClure, C. McBride, J. Gupte, T. Rubano, D. Pruss, S.V. Tavtigian, D.H.-F. Teng, N. Adey, M. Staebell, K. Gumpper, R. Lundstrom, M. Hulick, M. Kelly, J. Holmen, B. Lingenfelter, S. Manley, F. Fujimura, M. Luce, B. Ward, L. Cannon-Albright, L. Steele, K. Offit, T. Gilewski, L. Norton, K. Brown, C. Schulz, H. Hampel, A. Schluger, E. Giulotto, W. Zoli, A. Ravaioli, H. Nevanlinna, S. Pyrhonen, P. Rowley, J.L. Scalia, R. Michaelson, R.J. Scott, R. Radice, M.A. Pierotti, J.E. Garber, C. Isaacs, B. Peshkin, M.E. Lippman, M.H. Dosik, M.A. Caligo, R.M. Greenstein, R. Pilarski, B. Weber, R. Burgemeister, T.S. Frank, M.H. Skolnick, S. Thomas, BRCA1 sequence analysis in women at high risk for susceptibility mutations, J. Am. Med. Assoc. 278 (1997) 1242–1250. M. Santarosa, A. Viel, R. Dolcetti, D. Crivellari, M.D. Magri, M.A. Pizzichetta, M.G. Tibiletti, A. Gallo, S. Tumolo, L. Del Tin, M. Boiocchi, Low incidence of BRCA1 mutations among Italian families with breast and ovarian cancer, Int. J. Cancer 78 (1998) 581–586. N. Arnold, E. Gross, U. Schwarz-Boeger, J. Pfisterer, W. Jonat, M. Kiechle, A highly sensitive, fast, and economical technique for mutation analysis in hereditary breast and ovarian cancers, Hum. Mutat. 14 (1999) 333–339. L. Cortesi, D. Turchetti, C. Bertoni, R. Bellei, L. Mangone, M. Vinceti, M. Federico, V. Silingardi, S. Ferrari, Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations, Genes Chromo. Cancer 27 (2000) 130–135. B. Gorski, T. Byrski, T. Huzarski, A. Jakubowska, J. Menkiszak, J. Gronwald, A. Pluzanska, M. Bebenek, L. Fischer-Maliszewska, E. Grzybowska, S.A. Narod, J. Lubinski, Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer, Am. J. Hum. Genet. 66 (2000) 1963–1968.

197

[30] E. Gross, N. Arnold, K. Pfeifer, K. Bandick, M. Keichle, Identification of specific BRCA1 and BRCA2 variants by DHPLC, Hum. Mutat. 16 (2000) 345–353. [31] G. Kijima, Y. Murakami, N. Ohuchi, S. Satomi, T. Sekiya, Nonsense mutation at codon 63 of the BRCA1 gene in Japanese breast cancer patients, Jpn. J. Cancer Res. 89 (1998) 837–841. [32] T.I. Andersen, H.G. Eiken, F. Couch, G. Kaada, M. Skrede, H. Johnsen, T.A. Aloysius, K.M. Tveit, L. Tranebjaerg, A. Dorum, P. Moller, B.L. Weber, A.-L. Borresen-Dale, Constant denaturant gel electrophoresis (CDGE) in BRCA1 mutation screening, Hum. Mutat. 11 (1998) 166–174. [33] M.A. Caligo, C. Ghimenti, G. Cipollini, S. Ricci, I. Brunetti, V. Marchetti, R. Olsen, S. Neuhausen, D. Shattuck-Eidens, P.F. Conte, M.H. Skolnick, G. Bevilacqua, BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations, Oncogene 13 (1996) 1483– 1488. [34] O. Diez, J. Cortes, M. Domenech, J. Brunet, E. Del Rio, C. Pericay, J. Sanz, C. Alonso, M. Baiget, BRCA1 mutation analysis in 83 Spanish breast/ovarian cancer families, Int. J. Cancer 83 (1999) 465–469. [35] S.A. Gayther, P. Russell, P. Harrington, A.C. Antoniou, D.F. Easton, B.A.J. Ponder, The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes, Am. J. Hum. Genet. 65 (1999) 1021–1029. [36] R. Shiri-Sverdlov, P. Oefner, L. Green, R.G. Baruch, T. Wagner, A. Kruglikova, S. Haitchick, R.M.W. Hofstra, M.Z. Papa, I. Mulder, S. Rizel, R.B.B. Sade, E. Dagan, Z. Abdeen, B. Goldman, E. Friedman, Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer, Hum. Mutat. 16 (2000) 491–501. [37] Q. Gao, G. Tomlinson, S. Das, S. Cummings, L. Sveen, J. Fackenthal, P. Schumm, O.I. Olopade, Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer, Hum. Genet. 107 (2000) 186–191. [38] J.-H. Sng, J. Chang, R. Feroze, N. Rahman, W. Tan, S. Lim, M. Lehnert, S. van der Pool, J. Wong, The prevalence of BRCA1 mutations in Chinese patients with early onset breast cancer and affected relatives, Br. J. Cancer 82 (2000) 538–542. [39] F. Durocher, D. Shattuck-Eidens, M. McClure, F. Labrie, M.H. Skolnick, D.E. Goldgar, J. Simard, Comparison of BRCA1 polymorphisms, Hum. Mol. Genet. 5 (1996) 835– 842. [40] M.C. Southey, A.A. Tesoriero, C.R. Andersen, K.M. Jennings, S.M. Brown, G.S. Dite, M.A. Jenkins, R.H. Osborne, J.A. Maskiell, L. Porter, G.G. Giles, M.R.E. McCredie, J.L. Hopper, D.J. Venter, BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer, Br. J. Cancer 79 (1999) 34–39. [41] S.A. Janezic, A. Ziogas, L.M. Krumroy, M. Krasner, S.J. Plummer, P. Cohen, M. Gildea, D. Barker, R. Haile, G.

198

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50] [51]

[52]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200 Casey, H. Anton-Culver, Germline BRCA1 alterations in a population-based series of ovarian cancer cases, Hum. Mol. Genet. 8 (1999) 889–897. T. Katagiri, M. Emi, I. Ito, K. Kobayashi, M. Yoshimoto, T. Iwase, F. Kasumi, Y. Miki, M.H. Skolnick, Y. Nakamura, Mutations in the BRCA1 gene in Japanese breast cancer patients, Hum. Mutat. 7 (1996) 334–339. H. Ozdag, M. Tez, I. Sayek, M. Muslumanoglu, O. Tarcan, F. Icli, M. Ozturk, T. Ozcelik, Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients, Eur. J. Cancer 36 (2000) 2076–2082. A.M. Dunning, M. Chiano, N.R. Smith, J. Dearden, M. Gore, S. Oakes, C. Wilson, M. Stratton, J. Peto, D. Easton, D. Clayton, B.A. Ponder, Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population, Hum. Mol. Genet. 6 (1997) 285–289. E.L. Goode, A.M. Dunning, B. Kuschel, C.S. Healey, N.E. Day, B.A.J. Ponder, D.F. Easton, P.P.D. Pharoah, Effect of germ-line genetic variation on breast cancer survival in a population-based study, Cancer Res. 62 (2002) 3052–3057. A. Hadjisavvas, A. Adamou, C.O.D. Phanis, C.M. Todd, P. Kitsios, K. Kyriacou, C.G. Christodoulou, Q356R and S1512I are BRCA1 variants that may be associated with breast cancer in a Cypriot family, Oncol. Rep. 9 (2002) 383–386. A. Markoff, H. Sormbroen, N. Bogdanova, S. PreislerAdams, V. Ganev, B. Dworniczak, J. Horst, Comparison of conformation-sensitive gel electrophoresis and single-strand conformation polymorphism analysis for detection of mutations in the BRCA1 gene using optimized conformation analysis protocols, Eur. J. Hum. Genet. 6 (1998) 145–150. Y. Miki, J. Swensen, D. Shattuck-Eidens, P.A. Futreal, K. Harshman, S. Tavtigian, Q. Liu, C. Cochran, L.M. Bennett, W. Ding, R. Bell, J. Rosenthal, C. Hussey, T. Tran, M. McClure, C. Frye, T. Hattier, R. Phelps, A. Haugen-Strano, H. Katcher, K. Yakumo, Z. Gholami, D. Shaffer, S. Stone, S. Bayer, C. Wray, R. Bogden, P. Dayananth, J. Ward, P. Tonin, S. Narod, P.K. Bristow, F.H. Norris, L. Helvering, P. Morrison, P. Rosteck, M. Lai, J.C. Barrett, C. Lewis, S. Neuhausen, L. Cannon-Albright, D. Goldgar, R. Wiseman, A. Kamb, M.H. Skolnick, A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1, Science 266 (1994) 66–71. J.P. Geisler, M.A. Hatterman-Zogg, J.A. Rathe, T.A. Lallas, P. Kirby, R.E. Buller, Ovarian cancer BRCA1 mutation detection: protein truncation test (PTT) outperforms single strand conformation polymorphism analysis (SSCP), Hum. Mutat. 18 (2001) 337–344. Whitehead Institute For Biomedical Research (http://wwwgenome.wi.mit.edu/). A. Ghaderi, A. Talei, S. Farjadian, A. Mosalaei, M. Doroudchi, H. Kimura, Germline BRCA1 mutations in Iranian women with breast cancer, Cancer Lett. 165 (2001) 87–94. J.M. Lancaster, A. Berchuck, P.A. Futreal, R.W. Wiseman, Dideoxy fingerprinting assay for BRCA1 mutation analysis, Mol. Carcin. 17 (1997) 176–179.

[53] JCIB SNP database (http://snp.ims.u-tokyo.ac.jp). [54] F.B.L. Hogervorst, R.S. Cornelis, M. Bout, M. van Vliet, J.C. Oosterwijk, R. Olmer, B. Bakker, J.G.M. Klijn, H.F.A. Vasen, H. Meijers-Heijboer, F.H. Menko, C.J. Cornelisse, J.T. den Dunnen, P. Devilee, G.-J.B. van Ommen, Rapid detection of BRCA1 mutations by the protein truncation test, Nat. Genet. 10 (1995) 208–212. [55] D.F. Barker, E.R. Almeida, G. Casey, P.R. Fain, S.Y. Liao, I. Masunaka, B. Noble, T. Kurosaki, H. Anton-Culver, BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype, Genet. Epi. 13 (1996) 595–604. [56] L. Theodor, R. Bar-Sade, A. Kruglikova, G. Ben-Baruch, S. Risel, R. Shiri-Sverdlov, G. Hirsh Yechezkel, B. Modan, M.Z. Papa, G. Rechavi, E. Friedman, An identical novel mutation in BRCA1 and a common haplotype in familial ovarian cancer in non-Ashkenazi Jews, Br. J. Cancer 77 (1998) 1880–1883. [57] Whitehead Institute For Biomedical Research/MIT Center for Genome Research, Affymetrix data reported on NCBI website: http://www.ncbi.nlm.nih.gov/SNP/. [58] D. Shen, Y. Wu, M. Subbarao, H. Bhat, R. Chillar, J.V. Vadgama, Mutation analysis of BRCA1 gene in African– American patients with breast cancer, J. Natl. Med. Assoc. 92 (2000) 29–35. [59] M. Matsushima, K. Kobayashi, M. Emi, H. Saito, J. Saito, K. Suzumori, Y. Nakamura, Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation, Hum. Mol. Genet. 4 (1995) 1953–1956. [60] C.A. Bandera, M.G. Muto, J.O. Schorge, R.S. Berkowitz, S.C. Rubin, S.C. Mok, BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum, Obstet. Gynecol. 92 (1998) 596–600. [61] UCLA-DOE Laboratory for Structural Biology and Molecular Medicine (http://www.bioinformatics.ucla.edu/). [62] P. Huusko, K. Paakkonen, V. Launonen, M. Poyhonen, G. Blanco, A. Kauppila, U. Puistola, H. Kiviniemi, M. Kujala, J. Leisti, R. Winqvist, Evidence of founder mutations in Finnish BRCA1 and BRCA2 families, Am. J. Hum. Genet. 62 (1998) 1544–1548. [63] N. Hu, G. Li, W.J. Li, C. Wang, A.M. Goldstein, Z.Z. Tang, M.J. Roth, S.M. Dawsey, J. Huang, Q.H. Wang, T. Ding, C. Giffen, P.R. Taylor, M.R. Emmert-Buck, Infrequent mutation in the BRCA2 gene in esophageal squamous cell carcinoma, Clin. Cancer Res. 8 (2002) 1121–1126. [64] F.J. Couch, L.M. Farid, M.L. De Shano, S.V. Tavtigian, K. Calzone, L. Campeau, Y. Peng, B. Bogden, Q. Chen, S. Neuhausen, D. Shattuck-Eidens, A.K. Godwin, M. Daly, D.M. Radford, S.D. Sedlacek, J. Rommens, J. Simard, J. Garber, S. Merajver, B.L. Weber, BRCA2 germline mutations in male breast cancer cases and breast cancer families, Nat. Genet. 13 (1996) 123–125. [65] C.S. Healey, A.M. Dunning, M.D. Teare, D. Chase, L. Parker, J. Burns, J. Chang-Claude, A. Mannermaa, V. Kataja, D.G. Huntsman, P.D.P. Pharoah, R.N. Luben, D.F. Easton, B.A.J. Ponder, A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability, Nat. Genet. 26 (2000) 362–364.

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200 [66] The SNP Consortium (http://snp.cshl.org/). [67] K.E. Malone, J.R. Daling, C. Neal, N.M. Suter, C.A. O’Brien, K. Cushing-Haugen, T.J. Jonasdottir, J.D. Thompson, E.A. Ostrander, Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases, Cancer 88 (2000) 1393–1402. [68] M. Santarosa, R. Dolcetti, M.D. Magri, D. Crivellari, M.G. Tibiletti, A. Gallo, S. Tumolo, L.D. Puppa, D. Furlan, M. Boiocchi, A. Viel, BRCA1 and BRCA2 genes: role in hereditary breast and ovarian cancer in Italy, Int. J. Cancer 83 (1999) 5–9. [69] T. Peelen, M. van Vliet, A. Bosch, G. Bignell, H.F.A. Vasen, J.G.M. Klijn, H. Meijers-Heijboer, M. Stratton, G.-J.B. van Ommen, C.J. Cornelisse, P. Devilee, Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families, Br. J. Cancer 82 (2000) 151–156. [70] L.C. Verhoog, C.T.M. Brekelmans, C. Seynaeve, G. Dahmen, A.N. van Geel, C.C.M. Bartels, M.M.A. Tilanus-Linthorst, A. Wagner, P. Devilee, D.J.J. Halley, A.M.W. van den Ouweland, E.J. Meijers-Heijboer, J.G.M. Klijn, Survival in hereditary breast cancer associated with germline mutations of BRCA2, J. Clin. Oncol. 17 (1999) 3396–3402. [71] B. Kuschel, A. Auranen, S. McBride, K.L. Novik, A. Antoniou, J.M. Lipscombe, N.E. Day, D.F. Easton, B.A.J. Ponder, P.D.P. Pharoah, A. Dunning, Variants in DNA double-strand break repair genes and breast cancer susceptibility, Hum. Mol. Genet. 11 (2002) 1399–1407. [72] University of Washington Genome Centre (http://www. genome.washington.edu/projects/egpsnps/). [73] D.M. Severin, T. Leong, B. Cassidy, H. Elsaleh, L. Peters, D. Venter, M. Southey, M. McKay, Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients, Int. J. Radiat. Oncol. Biol. Phys. 50 (2001) 1323–1331. [74] Environmental Genome Project database (http://egp.gs. washington.edu/). [75] S. Sunyaev, J. Hanke, D. Brett, A. Aydin, I. Zastrow, W. Lathe, P. Bork, J. Reich, Individual variation in protein-coding sequences of human genome, Adv. Protein Chem. 54 (2000) 409–437. [76] M. O’Driscoll, K.M. Cerosaletti, P.-M. Girard, Y. Dai, M. Stumm, B. Kysela, B. Hirsch, A. Gennery, S.E. Palmer, J. Seidel, R.A. Gatti, R. Varon, M.A. Oettinger, H. Neitzel, P.A. Jeggo, P. Concannon, DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency, Mol. Cell 8 (2001) 1175–1185. [77] Genaissance Pharmaceuticals Inc. (http://www.genaissance. com/). [78] T. Fukuda, T. Sumiyoshi, M. Takahashi, T. Kataoka, T. Asahara, H. Inui, M. Watatani, M. Yasutomi, N. Kamada, K. Miyagawa, Alterations of the double-strand break repair gene MRE11 in cancer, Cancer Res. 61 (2001) 23–26. [79] G.S. Stewart, R.S. Maser, T. Stankovic, D.A. Bressan, M.I. Kaplan, N.G. Jaspers, A. Raams, P.J. Byrd, J.H. Petrini, A.M. Taylor, The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder, Cell 99 (1999) 577–587.

199

[80] S.A. Pitts, H.S. Kullar, T. Stankovic, G.S. Stewart, J.I.K. Last, T. Bedenham, S.J. Armstrong, M. Paine, L. Chessa, A.M.R. Taylor, P.J. Byrd, hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay, Hum. Mol. Genet. 10 (2001) 1155–1162. [81] R. Varon, A. Reis, G. Henze, H.G. von Einsiedel, K. Sperling, K. Seeger, Mutations in the Nijmegan breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL), Cancer Res. 61 (2001) 3570–3572. [82] D.J. Cutler, M.E. Zwick, M.M. Carrasquillo, C.T. Yohn, K.P. Tobin, C. Kashuk, D.J. Mathews, N.A. Shah, E.E. Eichler, J.A. Warrington, A. Chakravarti, High-throughput variation detection and genotyping using microarrays, Genome Res. 11 (2001) 1913–1925. [83] M. Kato, K. Yano, F. Matsuo, H. Saito, T. Katagiri, H. Kurumizaka, M. Yoshimoto, F. Kasumi, F. Akiyama, G. Sakamoto, H. Nagawa, Y. Nakamura, Y. Miki, Identification of Rad51 alteration in patients with bilateral breast cancer, J. Hum. Genet. 45 (2000) 133–137. [84] D.W. Bell, D.C.R. Wahrer, D.H. Kang, M.S. MacMahon, M.G. FitzGerald, C. Ishioka, K.J. Isselbacher, M. Krainer, D.A. Haber, Common nonsense mutations in RAD52, Cancer Res. 59 (1999) 3883–3888. [85] B.N. Ford, C.C. Ruttan, V.L. Kyle, M.E. Brackley, B.W. Glickman, Identification of single nucleotide polymorphisms in human DNA repair genes, Carcinogenesis 21 (2000) 1977–1981. [86] M. Matsuda, K. Miyagawa, M. Takahashi, T. Fukuda, T. Kataoka, T. Asahara, H. Inui, M. Watatani, M. Yasutomi, N. Kamada, K. Dohi, K. Kamiya, Mutations in the RAD54 recombination gene in primary cancers, Oncogene 18 (1999) 3427–3430. [87] Wellcome Trust Sanger Institute (http://www.sanger.ac.uk/). [88] T. Hiramoto, T. Nakanishi, T. Sumiyoshi, T. Fukuda, S. Matsuura, H. Tauchi, K. Komatsu, Y. Shibasaki, H. Inui, M. Watatani, M. Yasutomi, K. Sumii, G. Kajiyama, N. Kamada, K. Miyagawa, K. Kamiya, Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer, Oncogene 18 (1999) 3422–3426. [89] Stanford Human Genome Center (http://www-shgc.stanford. edu/). [90] S.Z. Abdel-Rahman, A.S. Soliman, M.L. Bondy, S. Omar, S.A. El-Badawy, H.M. Khaled, I.A. Seifeldin, B. Levin, Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt, Cancer Lett. 159 (2000) 79–86. [91] G.L. David-Beabes, S.J. London, Genetic polymorphism of XRCC1 and lung cancer risk among African–Americans and Caucasians, Lung Cancer 34 (2001) 333–339. [92] S.-U. Kim, S.K. Park, K.-Y. Yoo, K.-S. Yoon, J.Y. Choi, J.-S. Seo, W.-Y. Park, J.-H. Kim, D.-Y. Noh, S.-H. Ahn, K.-J. Choe, P.T. Strickland, A. Hirvonen, D. Kang, XRCC1 genetic polymorphism and breast cancer risk, Pharmacogenetics 12 (2002) 335–338. [93] R.M. Lunn, R.G. Langlois, L.L. Hsieh, C.L. Thompson, D.A. Bell, XRCC1 polymorphisms: effects on aflatoxin B1-DNA

200

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

C.C. Ruttan, B.W. Glickman / Mutation Research 509 (2002) 175–200 adducts and glycophorin A variant frequency, Cancer Res. 59 (1999) 2557–2561. A.F. Olshan, M.A. Watson, M.C. Weissler, D.A. Bell, XRCC1 polymorphisms and head and neck cancer, Cancer Lett. 178 (2002) 181–186. H. Shen, Y. Xu, Y. Qian, R. Yu, Y. Qin, L. Zhou, X. Wang, M.R. Spitz, Q. Wei, Polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population, Int. J. Cancer 15 (2000) 601–606. M.R. Shen, I.M. Jones, H. Mohrenweiser, Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans, Cancer Res. 58 (1998) 604–608. E.M. Sturgis, E.J. Castillo, L. Li, R. Zheng, S.A. Eicher, G.L. Clayman, S.S. Strom, M.R. Spitz, Q. Wei, Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck, Carcinogenesis 20 (1999) 2125–2129. J. Tuimala, G. Szekely, S. Gundy, A. Hirvonen, H. Norppa, Genetic polymorphisms of DNA repair and xenobioticmetabolizing enzymes: role in mutagen sensitivity, Carcinogenesis 23 (2002) 1003–1008. S.L. Winsey, N.A. Haldar, H.P. Marsh, M. Bunce, S.E. Marshall, A.L. Harris, F. Wojnarowska, K.I. Welsh, A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer, Cancer Res. 60 (2000) 5612–5616. K.K. Divine, F.D. Gilliland, R.E. Crowell, C.A. Stidley, T.J. Bocklage, D.L. Cook, S.A. Belinsky, The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung, Mutat. Res. 461 (2001) 273–278. E. Duell, J. Wiencke, T. Cheng, A. Varkonyi, Z. Zuo, T. Ashok, E. Mark, J. Wain, D. Christiani, K. Kelsey,

[102]

[103]

[104]

[105]

[106]

[107]

[108]

Polymorphisms in the DNA repair gene XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells, Carcinogenesis 21 (2000) 965–971. J.J. Hu, T.R. Smith, M.S. Miller, H.W. Mohrenweiser, A. Golden, L.D. Case, Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity, Carcinogenesis 22 (2001) 917–922. G. Matullo, D. Palli, M. Peluso, S. Guarrera, S. Carturan, E. Celentano, V. Krogh, A. Munnia, R. Tumino, S. Polidoro, A. Piazza, P. Vineis, XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32 P-DNA adducts in a sample of healthy subjects, Carcinogenesis 22 (2001) 1437–1445. J.Y. Park, S.Y. Lee, H.-S. Jeon, N.C. Bae, S.C. Chae, S. Joo, C.H. Kim, J.-H. Park, S. Kam, I.S. Kim, T.H. Jung, Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer, Cancer Epi. Biomark. Prev. 11 (2002) 23–27. C.L. Relton, C.P. Daniel, D.S. Chase, J. Burn, E.J. Tawn, Polymorphisms of the DNA repair gene XRCC1 and the frequency of somatic mutations at the glycophorin A locus in newborns, Mutat. Res. 502 (2002) 61–68. S. Rafii, P. O’Regan, G. Xinarianos, I. Azmy, T. Stephenson, M. Reed, M. Meuth, J. Thacker, A. Cox, A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer, Hum. Mol. Genet. 11 (2002) 1433–1438. G.L. David-Beabes, R.M. Lunn, S.J. London, No association between the XPD (Lys751Gln) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk, Cancer Epi. Biomark. Prev. 10 (2001) 911–912. M. Kato, S. Iida, H. Komatsu, R. Ueda, Lack of ku80 alteration in multiple myeloma, Jpn. J. Cancer Res. 93 (2002) 359–362.