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Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.‐28A>G and c.‐7C>T) within the  MLH1  5′untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high‐throughput sequencing of the  MLH1  locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.‐28A>G and c.‐7C>T variants were the only potentially pathogenic alterations within the  MLH1  gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild‐type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the  MLH1  promoter. We propose that these variants may be pathogenic due to constitutional partial loss of  MLH1  expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the  MLH1  5′UTR in the pathogenesis of Lynch syndrome.

Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression