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Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including  MSH2, MSH6, PMS2 , and  MLH1 . This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the  MSH2  gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of  MSH2  exon 11, so that the predicted products of the mutant  MSH2  mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that  MSH2  mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the  MSH2  gene causes LS and reaffirms the importance of genetic testing for LS.

A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome