title: BRCA2Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.
abstract: Breast cancer risks conferred by many germline missense variants in theBRCA1andBRCA2genes, 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.
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authors.initials: H
authors.lastname: Vrieling
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.|Department of Oncologic Science, University of South Florida, Tampa, Florida.
authors.forename: Alvaro N A
authors.initials: ANA
authors.lastname: Monteiro
authors.affiliation: Huntsman Cancer Institute and Department of Dermatology, University of Utah, Salt Lake City, Utah.
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Genotoxic Stress and Cancer, Institut Curie, Orsay, France.
authors.forename: Aura
authors.initials: A
authors.lastname: Carreira
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maaike P G
authors.initials: MPG
authors.lastname: Vreeswijk
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. couch.fergus@mayo.edu.|Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D012306:Risk
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human