Novel MSH2 frameshift variant (c.579delG) in a patient with suspected Lynch syndrome in China

To identify genetic variants in Chinese families with colorectal cancer.

Expression of mismatch-repair proteins was assessed via immunohistochemistry in three probands. Genetic variants were identified using whole-exome sequencing. In silico analyses were performed to assess the pathogenicity of these variants and their impacts on protein three-dimensional (3D) structure.

Two known missense variants (PMS2:NM_000535:exon11:c.1847T>C:p.V616A and PMS2:NM_000535:exon14:c.2444C>T:p.S815L) and a novel frameshift variant (MSH2:NM_000251:exon3:c.579delG:p.Q193fs) were found in families 1, 2, and 3, respectively. Protein 3D modeling showed that the c.2444C>T variant in the PMS2 protein locally altered the protein structure. In the wild-type PMS2 protein, S815 formed hydrogen bonds with N708 (3.1 Å), A811 (2.9 Å and 3.2 Å), and C812 (3.6 Å), whereas the mutant L815 did not form hydrogen bonds with nearby residues. The c.579delG variation in the MSH2 protein led to truncation from 934 amino acids to 212 amino acids, altered the sequence of the Domain 2 region, and caused the loss of Domains 3, 4, and 5.

The two missense variants of the PMS2 gene (PMS2:NM_000535:exon11:c.1847T>C:p.V616A and PMS2:NM_000535:exon14:c.2444C>T:p.S815L) were considered variants of uncertain significance, whereas the novel frameshift variant of the MSH2 gene (MSH2:NM_000251:exon3:c.579delG:p.Q193fs) was considered likely pathogenic.