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Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position –107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three −107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The −107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with −107C (P < 0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified −107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of −107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including −107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.