Lynch syndrome results from germline mutations in DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2) or epigenetic MSH2 inactivation via EPCAM deletion. Epigenetic MLH1 promoter methylation, the main cause of sporadic colorectal cancer with microsatellite instability, has unclear mechanisms. BRAF V600E mutations often precede MLH1 loss in serrated polyps. In most MLH1-deficient sporadic cancers, methylation is limited to tumour tissue, but constitutional MLH1 epimutation, found in normal tissues, increases cancer risk similar to Lynch syndrome, with early-onset colorectal/endometrial cancers and frequent metachronous tumours. These cases lack germline MLH1 mutations and somatic BRAF V600E, showing second MLH1 allele inactivation in tumours. Unlike Lynch syndrome, most epimutation patients lack a strong family cancer history. Inheritance varies: rare inconsistent transmission, autosomal dominant patterns, or common de novo cases without offspring transmission. Given the variable inheritance risks, patients with early-onset MLH1-deficient cancers require referral for genetic diagnosis and comprehensive counseling. Genetic workup should include promoter methylation analysis, particularly when no germline MLH1 mutation is identified.
