Uncovering Hereditary Risk: Germline Homologous Recombination Repair Variant Spectrum in a Large North Indian Cancer Cohort (INSIGHT-HRR).

Homologous recombination repair (HRR) pathway defects are critical drivers of hereditary cancers, yet population-specific prevalence data from India remain limited. Current testing practices disproportionately focus on BRCA1/2, potentially underidentifying patients with other HRR gene variants who could benefit from targeted therapies. A retrospective observational cohort study was conducted, analyzing 950 consecutive patients who underwent next generation sequencing-based germline testing at the Cancer Genetics Clinic, Mahamana Pandit Madanmohan Malaviya Cancer Centre, Varanasi. The core HRR panel included BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, CHEK2, BRIP1, BARD1, RAD50, NBN, MRE11, and FANCC. Of 950 patients analyzed, 364 (38.3%) harbored variants in HRR genes, with 266 (28%) carrying pathogenic/likely pathogenic (P/LP) variants. BRCA1 was the most frequently altered gene (182/266, 68.4% of P/LP variants), followed by BRCA2 (37/266, 13.9%). Combined BRCA1/2 genetic variants accounted for 219/266 (82.3 17%) of all P/LP variants. Non-BRCA HRR genes contributed 47/266 (17.6%) P/LP variants, with PALB2 being the most common (14/266, 5.2%). The study identified 98 variants of uncertain significance across the HRR genes. This large Indian cohort demonstrates a high prevalence of HRR gene alterations, with significant contribution from non-BRCA genes. These findings support the implementation of comprehensive HRR gene panels in Indian populations and highlight the therapeutic implications for poly (ADP-ribose) polymerase inhibitor and platinum-based treatment strategies.