Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076444 | SCV000107472 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Abrogated function & 2 MSI-H tumours |
| Ambry Genetics | RCV000218283 | SCV000274701 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-19 | criteria provided, single submitter | clinical testing | The p.E749K variant (also known as c.2245G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2245. The glutamic acid at codon 749 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in probands meeting Amsterdam and Bethesda criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13; Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702). In one family meeting Amsterdam criteria, the proband was diagnosed with a microsatellite unstable (MSI-H) colorectal cancer at age 29y and had six family members diagnosed with a Lynch syndrome-associated tumor (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17). In functional studies assessing repair activity, protein stability, mismatch binding, and ATP-catalyzed mismatch release activities, this alteration showed deficient repair and release activity (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17; Ollila S et al. Hum Mutat. 2008 Nov;29(11):1355-63). In addition, in a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001062435 | SCV001227235 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-01-28 | criteria provided, single submitter | clinical testing | Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 90942). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141, 15849733, 21120944, 21642682; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 749 of the MSH2 protein (p.Glu749Lys). Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18470917, 18951462, 21120944, 23690608, 30998989). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Myriad Genetics, |
RCV003452901 | SCV004186612 | likely pathogenic | Lynch syndrome 1 | 2023-08-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17101317, 18951462, 23690608, 30998989]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16216036, 17101317]. This variant is expected to disrupt protein structure [Myriad internal data]. |