A novel frameshift variant in MSH2 (p.Q170Rfs4) associated with suspected Lynch syndrome in a Chinese family

Objective This study aimed to characterize the pathogenic variants in three colon cancer families suspected of Lynch syndrome (LS), providing experimental evidence for precision screening and genetic counseling of the disease. Methods Three suspected LS families were first identified, and subsequently, immunohistochemical analysis was performed on colon tissue samples from probands to assess the expression of four DNA mismatch repair proteins. Whole-exome sequencing was conducted to screen for potential pathogenic variants within the families. The SWISS-MODEL online platform was used to predict the three-dimensional structures of the mutant and wild-type proteins based on bioinformatics analysis. The predicted structures were then visualized using PyMOL software. Results Two known MSH2 missense variants were identified: NM_000251.3:c.2633A>T:p.E878V in Family 1 and NM_000251.3:c.998G>A:p.C333Y in Family 2. A novel variant, designated as NM_000251.3:c.507del:p.Q170Rfs*4, was identified in the MSH2 gene of Family 3. This variant is caused by the deletion of an adenine at nucleotide position 507 within the MSH2 coding sequence, resulting in a frameshift. Consequently, glutamine at amino acid position 170 is altered to arginine, and a premature termination codon is introduced three residues downstream. This frameshift is predicted to generate a truncated protein of only 172 amino acids. Conclusion The MSH2 missense variant NM_000251.3:c.2633A>T:p.E878V was classified as a variant of uncertain significance regarding its role in LS. In contrast, the NM_000251.3:c.998G>A:p.C333Y missense variant was confirmed as pathogenic. Furthermore, the novel frameshift deletion NM_000251.3:c.507del:p.Q170Rfs*4 was also identified as a pathogenic variant.