Pan-cancer prevalence of microsatellite instability and Lynch syndrome in India.

Lynch syndrome (LS) is underdiagnosed in India, particularly outside colorectal cancer (CRC), because pan-cancer data on microsatellite instability (MSI), mismatch repair deficiency (MMRd), and germline predisposition remain limited. We consecutively recruited 519 patients with CRC and extracolonic cancers from 17 centres in India between 2019 and 2025, and applied a tumour-first approach using MSI testing by PCR-fragment length analysis (PCR-FLA) across all tumours, MMR immunohistochemistry (MMR-IHC) in extracolonic tumours, BRAF V600E testing in MSI-high (MSI-H) CRCs, and germline whole exome sequencing in MSI-H/BRAF wildtype CRCs and MSI-H/MMRd extracolonic tumours. MSI-H/MMRd status was identified in 24.9% (129/519) of tumours, and 51.2% (66/129) patients harboured pathogenic or likely pathogenic germline variants consistent with LS. CRC showed the highest LS yield, followed by endometrial and ovarian cancers, whereas several extracolonic tumour groups showed lower yields, in part reflecting cohort composition and tumour-specific MSI/MMRd prevalence. MLH1 accounted for most LS diagnoses (69.7%, 46/66) followed by MSH2 (18.2%, 12/66). Two recurrent MLH1 variants, c.306G>T and c.156delA, together accounted for 36.4% of all LS cases. Haplotype analysis supported c.156delA as a novel founder variant originating in Gujarat. Concordance between PCR-FLA and MMR-IHC in extracolonic tumours was 93.8%, supporting combined tumour-based screening in pan-cancer workflows. These findings establish the clinical utility of pan-cancer tumour-first LS detection in India and support broader implementation of reflex MSI/MMRd testing, germline confirmation, and cascade testing to improve surveillance, chemoprevention, and risk-reducing management in India.