BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

S. Cross | M. Beckmann | A. Børresen-Dale | Jingmei Li | K. Czene | P. Hall | J. Olson | F. Couch | H. Brenner | J. Chang-Claude | M. García-Closas | J. Benítez | G. Giles | C. Haiman | A. Spurdle | T. Dörk | M. Southey | A. Lophatananon | L. Marchand | A. Cox | D. Easton | A. Hollestelle | Chen-Yang Shen | A. Broeks | D. Lambrechts | J. Peto | D. Stram | H. Brauch | V. Kristensen | X. Shu | W. Zheng | H. Anton-Culver | P. Guénel | A. Dunning | P. Brennan | S. Sangrajrang | G. Chenevix-Trench | S. Bojesen | H. Nevanlinna | D. Kang | N. Bogdanova | P. Devilee | R. Milne | U. Hamann | A. Mannermaa | V. Kosma | M. Shah | K. Muir | A. Lindblom | K. Michailidou | J. Dennis | M. Schmidt | M. Bolla | Qin Wang | K. Aittomäki | H. Flyger | A. Rudolph | T. Truong | F. Marmé | B. Burwinkel | E. Sawyer | I. Tomlinson | I. Andrulis | G. Glendon | S. Margolin | V. Arndt | A. Swerdlow | J. Figueroa | R. Winqvist | K. Pylkäs | T. Brüning | P. Radice | P. Peterlongo | C. Seynaeve | A. Jakubowska | J. Lubiński | S. Slager | F. Fostira | K. Matsuo | Hidemi Ito | A. Wu | S. Teo | M. Hartman | H. Miao | M. Shrubsole | P. Pharoah | H. Darabi | M. Schoemaker | S. Neuhausen | C. V. van Asperen | D. Torres | A. Monteiro | L. Forétova | Ching-Yu Cheng | A. Osorio | J. Oosterwijk | F. Hogervorst | K. Claes | Ying Zheng | Jyh‐cherng Yu | H. Vrieling | M. U. Rashid | L. Walker | D. Goldgar | M. Vreeswijk | J. Collée | Chunling Hu | L. Varesco | L. van der Kolk | C. Aalfs | Ji-Yeob Choi | Åsa Ehlén | C. Olswold | J. Leary | J. Lilyquist | V. Rhenius | P. Fasching | E. Macháčková | L. Guidugli | A. Carreira | H. Shimelis | F. Calléja | B. Brouwers | Charlotte Martin | S. Moghadasi | Catharina von Nicolai | J. Hopper | H. Meeks | K. Lai | R. Mesman | E. Hallberg | I. dos-Santos-Silva | J. Hinton | L. Foretova | A. Monteiro | Hermela Shimelis

[1]  S. Kowalczykowski,et al.  BRCA2 regulates DMC1-mediated recombination through the BRC repeats , 2016, Proceedings of the National Academy of Sciences.

[2]  Dong Liang,et al.  BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. , 2016, Journal of the National Cancer Institute.

[3]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[4]  G. Hendriks,et al.  An Efficient Pipeline for the Generation and Functional Analysis of Human BRCA2 Variants of Uncertain Significance , 2014, Human mutation.

[5]  Ramaswamy K. Iyer,et al.  Germline Variation in Cancer-Susceptibility Genes in a Healthy, Ancestrally Diverse Cohort: Implications for Individual Genome Sequencing , 2014, PloS one.

[6]  F. Couch,et al.  BRCA1/2 sequence variants of uncertain significance: a primer for providers to assist in discussions and in medical management. , 2013, The oncologist.

[7]  P. Aloy,et al.  Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants , 2013, PloS one.

[8]  F. Couch,et al.  Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. , 2013, Cancer discovery.

[9]  Brooke L. Fridley,et al.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer , 2013, Nature Genetics.

[10]  Jaana M. Hartikainen,et al.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk , 2013, Nature Genetics.

[11]  Paolo Radice,et al.  A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. , 2013, Cancer research.

[12]  D. Pruss,et al.  Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. , 2012, Human molecular genetics.

[13]  F. Couch,et al.  BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk , 2012, Journal of Medical Genetics.

[14]  F. Couch,et al.  Classification of missense substitutions in the BRCA genes: A database dedicated to Ex‐UVs , 2012, Human mutation.

[15]  Sue Healey,et al.  ENIGMA—Evidence‐based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes , 2012, Human mutation.

[16]  Fergus J Couch,et al.  A review of a multifactorial probability‐based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) , 2012, Human mutation.

[17]  R. Byrd,et al.  A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. , 2011, Blood.

[18]  Dominique Vaur,et al.  Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes , 2011, European Journal of Human Genetics.

[19]  P. Radice,et al.  Unclassified variants in BRCA genes: guidelines for interpretation. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  S. Kowalczykowski,et al.  Purified human BRCA2 stimulates RAD51-mediated recombination , 2010, Nature.

[21]  J. Glover,et al.  Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. , 2010, Cancer research.

[22]  F. Couch,et al.  Assessment of functional effects of unclassified genetic variants , 2008, Human mutation.

[23]  S. Sharan,et al.  Mouse embryonic stem cell–based functional assay to evaluate mutations in BRCA2 , 2008, Nature Medicine.

[24]  Kiley J. Johnson,et al.  Functional assays for classification of BRCA2 variants of uncertain significance. , 2008, Cancer research.

[25]  F. Couch,et al.  Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios , 2008, Cancer informatics.

[26]  F. Couch,et al.  Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? , 2007, Breast Cancer Research.

[27]  Fergus J Couch,et al.  A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. , 2007, American journal of human genetics.

[28]  A. Spurdle,et al.  Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability , 2007, Breast Cancer Research and Treatment.

[29]  F. Couch,et al.  Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. , 2006, Molecular cell.

[30]  F. Couch,et al.  Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. , 2005, Cancer research.

[31]  F. Couch,et al.  Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. , 2004, American journal of human genetics.

[32]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[33]  Wen-Hwa Lee,et al.  BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. , 2002, Science.

[34]  B. Koller,et al.  Brca1 controls homology-directed DNA repair. , 1999, Molecular cell.

[35]  J. Ott,et al.  Strategies for multilocus linkage analysis in humans. , 1984, Proceedings of the National Academy of Sciences of the United States of America.