title: Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.
abstract: Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability.
authors.affiliation: Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Carvalho
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Marsillac
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Scott
authors.initials: S
authors.lastname: Grist
authors.forename: Ramona F
authors.initials: RF
authors.lastname: Swaby
authors.forename: Turan P
authors.initials: TP
authors.lastname: Urmenyi
authors.forename: Edson
authors.initials: E
authors.lastname: Rondinelli
authors.forename: Rosane
authors.initials: R
authors.lastname: Silva
authors.forename: Luis
authors.initials: L
authors.lastname: Gayol
authors.forename: Lisa
authors.initials: L
authors.lastname: Baumbach
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sutphen
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Pickard-Brzosowicz
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000502:physiology*; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D020125:Mutation, Missense; D013329:Structure-Activity Relationship
chemical_list: D019313:BRCA1 Protein