Einstein (Sao Paulo, Brazil) · 2026
Characterization of a novel MSH2 variant in Lynch syndrome: clinical data and complementary bioinformatics assessment.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Chami Anisse Marques, Zózimo Thalia Rodrigues de Souza, Matosinho Carolina Guimarães Ramos, Silva-Filho Agnaldo Lopes da, Carvalho Maria Raquel Santos, Braga Letícia da Conceição
Аннотация
OBJECTIVE: To 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.
METHODS: Clinical 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).
RESULTS: The 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.
CONCLUSION: No evidence of protein-rescuing mechanisms was found, supporting the classification of this variant as likely pathogenic/pathogenic.
METHODS: Clinical 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).
RESULTS: The 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.
CONCLUSION: No evidence of protein-rescuing mechanisms was found, supporting the classification of this variant as likely pathogenic/pathogenic.