In this study, we found that one in four Indian breast cancer patients carries an inherited genetic variant linked to cancer risk, with the majority of these variants occurring outside the well-known BRCA1 and BRCA2 genes. This finding underscores the urgent need to re-examine current genetic testing strategies in India, which continue to rely heavily on BRCA-only or hotspot-based testing.

By providing a high-resolution Germline mutational landscape in a large cohort of Indian breast cancer patients , this work lays critical groundwork for ancestry-aware precision oncology, family-based risk reduction strategies and improved chemotherapy safety. Our research team noted that expanding such studies nationally will be essential to developing genomic policies tailored to India’s unique population structure and disease burden. This finding were published in BMC Cancer, a prestigious, high‑impact specialist journal in oncology.

This study also highlights the importance of pharma cogenomics in chemotherapy safety. Clinically significant DPYD variants known to cause severe toxicity with fluoro pyrimidine drugs such as 5-FU and capecitabine were observed at measurable frequency in this Indian cohort. The researchers detected the c.1679T>G (HapB3) variant in 3.13 per cent and the c.1905+1G>A variant in 1.67 per cent of patients, supporting strong consideration for routine DPYD genotyping prior to treatment initiation.

The team examined 97 cancer susceptibility genes, including BRCA1, BRCA2 and 15 genes involved in the homologous recombination repair pathway. Variants were classified using internationally accepted ACMG/AMP guidelines. The researchers also assessed pharma cogenomic markers affecting chemotherapy safety, screened for actionable secondary findings in non-cancer genes, and compared variant frequencies with global populations using the gnomAD database to identify Indian- and South Asian–enriched variants. A special focus was placed on RECQL, an emerging breast cancer gene with highly population-specific patterns.

The study found that 24.6 per cent of patients carried at least one pathogenic or likely pathogenic variant. Only 8.35 per cent had BRCA1 or BRCA2 variants, while a significantly larger proportion (11.9 per cent), had inherited pathogenic variants in genes belonging to the homologous recombination repair pathway. Overall, 67 per cent of all positive findings occurred in non - BRCA genes, including MLH1, NF1, TP53 and RB1, demonstrating that the inherited landscape of breast cancer risk in India is far more complex than previously appreciated.

We identified multiple ancestry-specific pathogenic variants that were either absent or extremely rare in global datasets. These included an India-enriched BRCA1 variant and potential India-specific variants in the RECQL gene. Several RECQL variants commonly reported in studies from Quebec, Poland and China were not seen in the Indian cohort, highlighting strong regional and population-driven differences.