A novel stop-gain mutation in the MSH2 gene among a Persian family fulfilling classic Amsterdam criteria for Lynch syndrome

Lynch syndrome (LS) is the most common hereditary cancer predisposing syndrome whose molecular pathogenesis is germline mutations in at least one of the four DNA mismatch repair (MMR) genes including MLH1, MSH2, PMS2, and MSH6. We report in this article a new pathogenic variant of MSH2 gene which was found in a Persian family with LS.We designed a case series study for clinical and molecular screening of CRC patients at risk for LS in central Iran. Using Amsterdam II criteria (AC-II), 31 families were candidate for immunohistochemically staining (IHC-MMRs) and microsatellite instability (MSI) testing. Finally, 7 probands were diagnosed as MMR deficient and harbored genetic testing through next generation sequencing (NGS) of the candidate genes. Bioinformatic analysis was performed to identify pathogenic variants according to ACMG guidelines. A co-segregation analysis of the variant was run using genomic DNA of three first degree relatives of the proband, one affected and two others healthy. After NGS mutation analysis of MMR genes, a likely pathogenic-related variant was identified on the first exon of MSH2 gene on chromosome 2 (rs374127044) which had been caused by an A> T change on the first exon of MSH2 gene (NM_000251.2:c.364A> T). This heterogeneous mononucleotide substitution creates a stop codon-gained mutation. Sanger sequencing of an amplified genomic DNA segment including the variant revealed a similar heterogeneous variant in the proband’s affected father. But, none of two healthy sisters of the proband presented this variant. Given the lack of enough molecular and clinicopathologic information about LS affected families among Iranian populations, more evaluations are recommended to explore other pathogenic variants of MMR genes among Iranian LS families.

کلیدواژه ها:

mutation ، MSH2 gene ، Amsterdam criteria ، Lynch syndrome