A Novel Stop-Gain Mutation in MSH2 Gene Among a Persian Family Fulfilling Classic Amsterdam Criteria for Lynch Syndrome

Abstract

Purpose Lynch syndrome is the most common hereditary cancer syndromes due to a germline mutation in one of the mismatch-repair (MMR) genes. It results in early-onset colorectal cancer (CRC) and other Lynch-associated cancers in an autosomal dominant pattern. In this article, a new pathogenic variant in a Persian family with familial CRCs and positive Amsterdam II criteria has been described. Methods IHC-MMRs was done on tissue sections from tumor and its adjacent healthy tissue of the proband. Microsatellite instability (MSI) testing was also performed on DNA extracted from tumor and healthy tissue using Promega kit. Next Generation Sequencing (NGS) was finally done on genomic DNA of the proband using a 12-gene-panel including MMR genes. Variant filtering and prioritization were done using bioinformatics tools. Co-segregation analysis was used to evaluate the explored pathogenic variant. Results The proband was a 38-year woman at-diagnosis affected with CRC located in the sigmoid colon. The family history of cancer was observed in three successive generations. IHC was absent for MSH2 and MSH6, and MSI-High was reported from MSI testing. NGS analysis explored a new stop gained codon mutation on the first exon of MSH2 gene as a substitution of A to G MSH2: c.364A > T which was pathogenic according to the variant interpretation guidelines of American College of Medical Genetics and Genomics. Conclusion Revealing of a more obvious molecular feature of Lynch-syndrome among Iranian populations could lead to identification of at-risk people for early care and prevention of cancer.