BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

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Shimelis, Hermela ; Mesman, Romy LS ; Von, Nicolai Catharina ; Ehlen, Asa ; Guidugli, Lucia ; Martin, Charlotte ; Calléja, Fabienne MGR ; Meeks, Huong ; Hallberg, Emily ; Hinton, Jamie ; Lilyquist, Jenna ; Hu, Chunling ; Aalfs, Cora M ; Aittomäki, Kristiina ; Andrulis, Irene ; Anton-Culver, Hoda ; Arndt, Volker ; Beckmann, Matthias W ; Benitez, Javier ; Bogdanova, Natalia V ; Bojesen, Stig E ; Bolla, Manjeet Kaur ; Borresen-Dale, Anne-Lise ; Brauch, Hiltrud ; Brennan, Paul ; Brenner, Hermann ; Broeks, Annegien ; Brouwers, Barbara ; Brüning, Thomas ; Burwinkel, Barbara ... view all 135 authors (2017)
  • Publisher: Cancer research
  • Related identifiers: doi: 10.17863/CAM.9851
  • Subject: for kConFab/AOCS Investigators | for NBCS Collaborators

Breast cancer risks conferred by many germline missense variants in the $\textit{BRCA1}$ and $\textit{BRCA2}$ 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; $\textit{P}$ = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; $\textit{P}$ = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; $\textit{P}$ = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; $\textit{P}$ = 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. This work was supported in part by NIH grants CA116167, CA176785, CA192393, an NIH specialized program of research excellence (SPORE) in breast cancer to the Mayo Clinic (P50 CA116201), the Breast Cancer Research Foundation (to F.C. Couch), the ATIP-AVENIR CNRS/INSERM Young Investi- gator grant 201201, EC-Marie Curie Career Integration grant CIG293444, Institute National du CancerINCa-DGOS_8706 (to A. Carreira), the Dutch Cancer Society KWF (UL2012-5649 to M.P.G. Vreeswijk), the Australian National Health and Medical Research Council (ID#1010719), and The Cancer Council Queensland (ID#1086286 to A. Spurdle). BCAC data management was funded by Cancer Research UK (C1287/A10118 and C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175 to D.F. Easton). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (COGS; HEALTH-F2- 2009-223175 to P. Hall), Cancer Research UK (C1287/A10118, C1287/ A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 to D.F. Easton), the NIH (CA128978 to F.J. Couch), and Post-Cancer GWAS initiative (1U19 CA148537, C.A. Haiman; 1U19 CA148065, D.F. Easton; and 1U19 CA148112-the GAME-ON initiative to T.A. Sellers), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (to I. Andrulis), and the Breast Cancer Research Foundation (to F.J. Couch).
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