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

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.

Source: The American Journal of Human Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Lucia Guidugli, Hermela Shimelis, David L. Masica, Vernon S. Pankratz, Gary B. Lipton, Namit Singh, Chunling Hu, Alvaro N.A. Monteiro, Noralane M. Lindor, David E. Goldgar, Rachel Karchin, Edwin S. Iversen, Fergus J. Couch Tags: Article Source Type: research