Background:
Germline mutations in BRCA1 and BRCA2 genes are key risk factors for hereditary breast and ovarian cancer, accounting for 5-15% of cases globally. Limited data exist on their prevalence in Nepalese populations, where genetic testing is emerging. This study aims to describe the spectrum of BRCA1 and BRCA2 variants detected in women undergoing genetic testing in Nepal using next-generation sequencing (NGS).
 
Objectives:
This study aims to characterize the spectrum of germline BRCA1 and BRCA2 variants in high-risk Nepalese women using targeted next-generation sequencing. By identifying pathogenic mutations and variants of uncertain significance, the study seeks to provide insights into the genetic risk factors for hereditary breast and ovarian cancer in the Nepalese population and support the implementation of genetic counseling and personalized cancer prevention strategies.

Methods:
A descriptive case series was conducted on female patients referred for BRCA1 and BRCA2 germline mutation. Genomic DNA was extracted from peripheral blood samples and analyzed using the Oncomine BRCA Assay on the Ion GeneStudio S5 platform. Variant calling and annotation were performed using Ion Reporter software with ClinVar classification. Detected variants were categorized as pathogenic, likely benign, variants of uncertain significance (VUS), or negative.

Results:
Among the tested individuals, pathogenic mutations in the BRCA1 gene were found in some patients. These included frameshift and nonsense mutations such as c.1961delA (p. Lys654fs) and c.2214dup / c.2214_2215insT (p. Lys739Ter). These mutations are known to stop normal protein production and are strongly linked to an increased risk of breast and ovarian cancer.
One patient showed a BRCA2 missense variant (c.7937G>A; p. Cys2646Tyr), which was classified as a variant of uncertain significance (VUS). This means that its role in causing disease is not yet clearly known. Several other patients did not show any pathogenic mutations in either BRCA1 or BRCA2 genes.
Overall, the findings show that both disease-causing and uncertain BRCA variants are present among Nepalese women, while many individuals tested negative for harmful mutations.   

Conclusion:
This case series highlights the presence of clinically significant BRCA1 pathogenic variants and BRCA2 variants of uncertain significance among Nepalese women. The findings emphasize the importance of incorporating comprehensive BRCA genetic testing into clinical practice in Nepal for early risk assessment, genetic counseling, and personalized cancer prevention strategies. Larger population-based studies are warranted to better define the BRCA mutation spectrum in Nepal.