The pathogenic role of the BRCA2 c.7847C > T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition

Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the PS3, PM2, PM3, and PP3 criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a likely pathogenic variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.

Automated summary

Through genetic testing, a significant number of variants of unknown significance (VUSs) have been found in BRCA1/2, posing a challenge in clinical practice due to the uncertain contribution of these VUSs to cancer predisposition. In this study, a specific VUS, BRCA2 c.7847C>T (p.Ser2616Phe), was identified in 10 Japanese patients from seven families with breast or ovarian cancer. The variant was not found in global population databases and functional assays suggested its pathogenicity. The findings indicate that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a likely pathogenic variant specifically observed in the Japanese population, contributing to breast and ovarian cancer predisposition.