ClinVar

Description

This variant is a gross deletion of the genomic region encompassing exons 3-16 of the MSH2 gene. The 5' boundary is likely confined to intron 3. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. A similar deletion has been reported in an individual with clinical features of Lynch syndrome (PMID: 18566915). This variant deletes the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (deleted residues Ile216-Thr934) (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). This suggests that deletion of this region of the MSH2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.