The MSH2 c.793-1G>A variant disrupts normal splicing and is associated with Lynch syndrome

We reported a multi-generation Chinese family clinically diagnosed with LS. To identify the underlying pathogenic gene variants for LS in this family, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Microsatellite instability-high (MSI) testing and immunohistochemistry (IHC) revealed microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR). Sanger sequencing and PCR also validated the WES results. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant(c.793-1G>A) affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein.