Characterization of a novel MSH2 variant in Lynch syndrome: clinical data and complementary bioinformatics assessment.

objectiveTo describe the clinical characteristics and perform a multi-step bioinformatics evaluation of the pathogenicity of NM_000251.3(MSH2):c.1894_1898del (p.Ile633Lysfs*9), an MSH2 germline variant detected in a family with Lynch syndrome.

methodsClinical evaluation included description of phenotype, family history, and immunohistochemical characterization of the proband's tumors. For pathogenicity classification according to the American College of Genetics and Genomics/Association for Molecular Pathology (ACMG/APA) criteria, bioinformatics analyses included: (i) literature and database screening, searching for the variant allele frequency, case reports, or functional studies, including ClinVar, VarSome, Ensembl, PubMed, EVA, and ABraOM; (ii) prediction of variant impacts using ExPASy Translate, Pfam, and Modeller 9.24; and, (iii) mechanisms that could mitigate the effects of the variant included alternative splicing and exon skipping (UniProt and GTex) and nonsense-mediated decay (NMD; MutationTaster2021).

resultsThe proband, a 55-year-old female, was diagnosed with two metachronous colorectal cancers. Immunohistochemical analysis showed loss of expression ( MSH2 in one tumor, and MSH2 and MSH6 in the other). Seven deceased family members were diagnosed with cancer (four colorectal, one uterine, and two unspecified). This variant caused a stop codon in MSH2 exon 12 of 16. When translated, the protein loses 294 C-terminal residues, which may prompt protein degradation. If the mutated protein escapes degradation, dimerization and DNA-binding domains will be present. Therefore, negative dominance effects were possible. No isoforms ending in exon 12 have been identified in the literature or in RNA splicing databases. A stop codon before the last exon-exon boundary indicated the occurrence of NMD.

conclusionNo evidence of protein-rescuing mechanisms was found, supporting the classification of this variant as likely pathogenic/pathogenic.