Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001032802 | SCV001196109 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-06-08 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 9-16 of the MSH2 gene. The 5' boundary is likely confined to intron 8. 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. Similar deletions of exons 9-16 have been observed in several individuals affected with Lynch syndrome (PMID: 19459153, 17665423, 25559809, 14635101, 15475941, 16528605, 22658618). This deletion is expected to disrupt the C-terminal portion of of the MSH2 protein including the EXO1 interaction domain, ATPase, and helix-turn-helix domains, as well as, the C-terminal MSH6 and MSH3 interaction domains of the MSH2 protein (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. |