Familial Genetic Cancer Risk Assessment with respect to a Silent BRCA2 mutation

Abstract

Male Breast Cancer (BC) is relatively rarer, accounting for less than 1% of cancers in men. MBC is hereditary in nature and mainly attributed to BRCA1/2 germline 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 pathogenic BRCA2 variant (c.8754G>A, p.E2918E). Subsequently, 34 members of the extended family of the proband were tested for the BRCA2 variant by Sanger sequencing. 6 of the family members were identified as carriers of this BRCA2 variant. Of these, three presented with hereditary breast cancer and 3 were unaffected healthy carriers. In silico analysis for mechanistic insights in underlying pathogenicity revealed that the silent BRCA2 mutation is a spliceogenic variant that is likely to create an aberrant mRNA transcript via alternative splicing of BRCA2 gene. Our study demonstrates the clinical relevance of this silent BRCA2 mutation and emphasizes the need for further experimental studies to elucidate its functional role in breast cancer pathology.