Familial Genetic Cancer Risk Assessment with respect to a SilentBRCA2mutation

AbstractMale Breast Cancer (BC) is relatively rarer, accounting for less than 1% of cancers in men. MBC is hereditary in nature and mainly attributed toBRCA1/2germline mutations. Accordingly, National Comprehensive Cancer Network (NCCN) guidelines advise genetic counselling and testing for all cases of MBCs and their unaffected family members. In this report, we present an uncommon case of male patient primarily diagnosed with pancreatic cancer who later developed asynchronous bilateral hormone positive breast cancer. We describe the genetic screening and clinical management protocol for the proband and family members. Genetic testing with next generation sequencing by uses of a multi-gene germline mutation panel revealed a likely pathogenicBRCA2variant (c.8754G>A, p.E2918E). Subsequently, 34 members of the extended family of the proband were tested for theBRCA2variant by Sanger sequencing. 6 of the family members were identified as carriers of thisBRCA2variant. Of these, three presented with hereditary breast cancer and 3 were unaffected healthy carriers.In silicoanalysis for mechanistic insights in underlying pathogenicity revealed that the silentBRCA2mutation is a spliceogenic variant that is likely to create an aberrant mRNA transcript via alternative splicing ofBRCA2gene. Our study demonstrates the clinical relevance of this silentBRCA2mutation and emphasizes the need for further experimental studies to elucidate its functional role in breast cancer pathology.