Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer. However, many variants identified in this gene are often defined as variants of uncertain significance (VUS). In this study, we selected a variant in the 3′ untranslated region (UTR) of MSH2 (c*226A > G), identified in three affected members of a LS family and already reported in the literature as a VUS. Methods: The effect of this variant on the activity of the MMR complex was examined using a set of functional assays to evaluate MSH2 expression. Results: We found MSH2 was overexpressed compared to healthy controls, as determined by RTqPCR and Western blot analyses of total RNA and proteins, respectively, extracted from peripheral blood samples. These results were confirmed by luciferase reporter gene assays. Conclusions: We therefore speculated that, in addition to canonical inactivation via a gene mutation, MMR activity may also be modulated by changes in MMR gene expression.

Background: Lynch syndrome is associated with genetic variants in mismatch repair ( MMR ) genes. Pathogenic variants in the MLH1 and MSH2 genes occur in most families in which the phenotype is highly penetrant. These testing criteria are likely to miss individuals with Lynch syndrome due to the less penetrant MMR genes, such as MSH6, MLH3, MSH3, and PMS2 . So far, several mutations in the PMS2 gene have been described as responsible for the clinical manifestation of Lynch syndrome. Recent data have reported that families with atypical Lynch phenotype were found to have primarily monoallelic mutations in the PMS2 gene. Methods: We analyzed the PMS2 gene to detect mutations in members of 64 Lynch syndrome families by direct sequencing. Results: We report the identification of several genetic variants in patients with LS, of which three are novel variants. The carriers of these novel variants were also carried of other variants in PMS2 gene and/or in other MMR genes. Conclusion: Therefore, we think that these novel PMS2 variants may act in additive manner to manifestation LS phenotype.