Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001033647 | SCV001196954 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-26 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon(s) 8-16 of the MSH2 gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product. A similar copy number variant has been observed in individual(s) with Lynch syndrome (PMID: 15942939, 16837128). This variant disrupts the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain, which are important for proper dimerization and normal protein functioning (PMID: 9774676, 18822302, 17531815). While functional studies have not been performed to directly test the effect of this variant on MSH2 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ile883Leufs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |