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

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PURPOSE 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. METHODS 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 . RESULTS 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. CONCLUSION 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.

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