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.
Highlights
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
While pathogenic variants of the BRCA1 and BRCA2 genes account for about one fourth of all breast and ovarian cancer families1, variants of uncertain significance (VUS) are the result of a smaller fraction of all tests (2–20%)2,3 and cannot be used for identification of predisposed family members as long as their clinical relevance is clearly defined
During the molecular analysis of BRCA1/2 genes in more than 6,000 breast and/or ovarian cancer patients, we identified 15 families (0.25%) carrying the BRCA2 c.9227G>T variant
Summary
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. While pathogenic variants of the BRCA1 and BRCA2 genes account for about one fourth of all breast and ovarian cancer families1, VUS are the result of a smaller fraction of all tests (2–20%)2,3 and cannot be used for identification of predisposed family members as long as their clinical relevance is clearly defined. Predictive testing within families is only recommended for variants with a probability of pathogenicity higher than 95% (i.e. class 4 and 5 according to a widely used 5-tiered classification)4.
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