A Lynch syndrome patient with multiple cancers who was found to have a novel pathogenic variant generating aberrant splicing of MLH1.

Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by inactivating germline variants in DNA mismatch repair genes. Here, we describe a woman who developed colorectal, gastric, and endometrial cancers and was found to have a rare missense variant, MLH1:c.545G > T/p.Arg182Met. The variant, which was located at the last nucleotide of MLH1exon 6, was initially reported by a clinical testing laboratory as being a variant of uncertain significance. In silico analyses predicted that it would cause splicing aberration, and reverse-transcription polymerase chain reaction analysis of total RNA from the patient's peripheral blood cells identified an aberrant MLH1 transcript that skipped the entire exon 6 and caused generation of a premature stop codon (p.Glu153Phefs*8). In accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, we reclassified the variant as likely pathogenic. Further additional analysis enabled carrier diagnosis in the patient's relatives. Genetics summary Disorder: Lynch syndrome Ethnicity of the patient: Japanese Gene: MLH1 (19 exons) GenBank accession number: NM_000249.4 Chromosomal assignment: 3p21.3 Type of DNA variant: a germline splice aberration variant Mutation: c.545G > T in exon 6 of MLH1 Methods of mutation detection: PCR-sequencing, RT-PCR.