Aberrant splicing caused by a MLH1 splice donor site mutation found in a young Japanese patient with Lynch syndrome

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, characterized by predisposition to colorectal cancer and other associated cancers, is an autosomal-dominant disorder mainly caused by germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, and MSH6. Some mutations that disrupt splice donor or acceptor sites cause aberrant mRNA splicing. These mutations are generally considered as pathogenic ones, however, it is sometimes uneasy to accurately predict their pathogenicity without functional assays, particularly when the mutation is a single nucleotide substitution. In this report, we describe a 25-year-old patient with Lynch syndrome who carries a germline variant in a splice donor site of the MLH1 gene (c.790 + 5 G > T), which was first detected among Asian populations. The immunohistochemical analysis revealed loss of MLH1 protein expression in the tumor. Our splicing assay confirmed that the intronic MLH1 variant actually caused aberrant splicing, supporting its pathogenic effect. Our data accumulate more information on the genotype-phenotype relationships in patients with Lynch syndrome.