Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.

ABSTRACT: Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ?99% probability of pathogenicity, and 73 had ?95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to

SUBMITTER: Guidugli L 

PROVIDER: S-EPMC5985401 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature