Molecular Spectrum of Germline BRCA1 and BRCA2 Mutation in a Cohort of Indian Cancer Patients: A Report from Reference Laboratory

Background: Individuals harbouring BRCA1/2 pathogenic germline mutations have high lifetime risks of breast, ovarian, and prostate cancer. In this study, we aimed to identify BRCA1/2 mutation frequency and spectrum in 350 Indian cases fulfilling the NCCN criteria. Methodology: The BRCA1/2 gene sequencing was done by NGS. Results: Among the 350 cases, 85 (24.2%) carried a pathogenic variant in BRCA1 (n=60) or BRCA2 (n=25) gene. The frequencies of BRCA mutations were higher in ovarian cancer than breast cancer (26.7% vs. 20%) although not significant. Furthermore, one case each of prostate and pancreatic cancer harboured BRCA mutation. Majority of the mutations (53%) were located in the BCCR and OCCR region in both BRCA1/2 genes. A spectrum of 70 unique pathogenic variants (46 in BRCA1 and 24 in BRCA2) was identified in 85 cases. Interestingly, 7 BRCA1 and one BRCA2 mutations were recurrent, accounting for 15.2% and 4.2% of all mutations. The variants c.68_69delAG and c.4508C>A in BRCA1 and c.9380G>A in BRCA2 appears to be the hotspot mutation. Notably, we identified seven novel variants (4 in BRCA1 and 3 in BRCA2 gene) which were not reported till date. VUS was identified in 5.1% cases and was predominantly seen in BRCA2 gene (83%, 15/18). Conclusion: These results demonstrate that the prevalence of BRCA mutation in Indian patients varies considerably and is similar to global reports. The molecular spectrum of BRCA variants is also dissimilar, and requires its cautious classification. The current study identified novel variants which added new insights into the genetic heterogeneity of the BRCA gene. Keywords: BRCA1/2 Gene • Germline mutation • Next-Generation Sequencing (NGS)