Abstract
Classification of variants in the BRCA1 and BRCA2 genes has a major impact on the clinical management of subjects at high risk for breast and ovarian cancer. The identification of a pathogenic variant allows for early detection/prevention strategies in healthy carriers as well as targeted treatments in patients affected by BRCA-associated tumors. The BRCA2 c.9227G>T p.(Gly3076Val) variant recurs in families from Northeast Italy and is rarely reported in international databases. This variant substitutes the evolutionary invariant glycine 3076 with a valine in the DNA binding domain of the BRCA2 protein, thus suggesting a high probability of pathogenicity. We analysed clinical and genealogic data of carriers from 15 breast/ovarian cancer families in whom no other pathogenic variants were detected. The variant was shown to co-segregate with breast and ovarian cancer in the most informative families. Combined segregation data led to a likelihood ratio of 81,527:1 of pathogenicity vs. neutrality. We conclude that c.9227G>T is a BRCA2 pathogenic variant that recurs in Northeast Italy. It can now be safely used for the predictive testing of healthy family members to guide preventive surgery and/or early tumor detection strategies, as well as for PARP inhibitors treatments in patients with BRCA2-associated tumors.