Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076382 | SCV000107408 | likely pathogenic | Lynch syndrome 1 | 2018-03-09 | reviewed by expert panel | curation | Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.9707 |
| Ambry Genetics | RCV002415563 | SCV002727732 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-08-01 | criteria provided, single submitter | clinical testing | The p.G692V variant (also known as c.2075G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2075. The glycine at codon 692 is replaced by valine, an amino acid with dissimilar properties. This variant has been reported in several Lynch syndrome families meeting Amsterdam I or II criteria (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Casey G et al. JAMA, 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This variant has also been reported in conjunction with an EPCAM pathogenic gross deletion in an individual diagnosed with synchronous colorectal cancers and polyposis at age 9; maternal family history was consistent with Lynch syndrome and included several relatives heterozygous for p.G692V (Li-Chang HH et al. J. Clin. Pathol., 2013 Jul;66:631-3). Based on internal structural analysis, this variant is more disruptive than multiple known pathogenic variants in this region (Gupta S et al. Nat. Struct. Mol. Biol., 2011 Dec;19:72-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV005089518 | SCV005834013 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-05-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 692 of the MSH2 protein (p.Gly692Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome or constitutional mismatch repair deficiency syndrome (PMID: 12624141, 15713769, 19698169, 21879275, 23454724, 29212164). ClinVar contains an entry for this variant (Variation ID: 90880). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612836, 17720936, 26951660, 28577310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001355702 | SCV001550658 | pathogenic | not provided | no assertion criteria provided | clinical testing | The p.Gly692Val variant has been reported in the literature in 5/624 probands who had a diangosis of colorectal cancer. Our lab has identified this variant in 2 families, both who met the clinical criteria for HNPCC, and one whom had multiple tumors and all were MSH2 defcient by immunohistochemistry; this individual also had a striking family history of HNPCC related tumours, increasing likelihood that this variant is pathogenic. In addition, a recent study showed that the variant was identified in a family with Lynch Syndrome (Canard 2011). This variant is listed in dbSNP database from a 'clinical source' (ID#: rs63751432) but no frequency information was provided. The Gly692 residue is conserved across mammals and other species and computational analyses (AlignGVGD and SIFT) suggest that this variant may impact the protein function. In one study, this variant was reported as a VUS based on insufficient data (Casey 2005) but was associated with loss of MSH2 protein by immunohistochemical analysis, suggesting a pathogenic role for this variant. However, in a microsatellite instability study, this variant was also classified as variant of unknown significance (VUS) (Mangold 2005). Further, in another study using multivariate analysis of protein polymorphisms (MAPP)-mismatch repair (MMR), this variant has been also classified as VUS (Chao 2008), but this information is not sufficient to make a conclusion. In summary, based on the above information, this variant is considered pathogenic. |