Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000490880 | SCV000580439 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-22 | criteria provided, single submitter | clinical testing | The p.G692W pathogenic mutation (also known as c.2074G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2074. The glycine at codon 692 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected as a germline and a somatic mutation in multiple patients with mismatch repair-deficient, MSI-H colorectal cancers (Haraldsdottir S et al. Gastroenterology 2014 Dec;147:1308-1316.e1; Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095; LaDuca H et al. PLoS One. 2017 Feb 2;12(2):e0170843). In addition, using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as likely pathogenic (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). Two other alterations at the same codon, p.G692R and p.G692V, have been detected in several Lynch/HNPCC syndrome families with mismatch repair-deficient, MSI-H tumors (Isidro et al. Hum Mut. 2000 Jan; 15(1):116; 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), and the p.G692R alteration has been shown to have reduced protein expression and impaired function (Gammie et al. Genetics. 2007 Oct; 177(2): 707-21; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).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. |
| Center for Human Genetics, |
RCV000659883 | SCV000781775 | uncertain significance | Lynch syndrome 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| University of Washington Department of Laboratory Medicine, |
RCV000664310 | SCV000788242 | likely pathogenic | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH2 NM_000251.2:c.2074G>T has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. In-silico prediction scores using MAPP and PolyPhen2 give this variant a high likelihood of being pathogenic. This variant has been reported by another laboratory to segregate with Lynch syndrome associated cancers in one family. In addition, a variant at the same position (p.G692R, NM_000179.2:c.2074 G to C) is classified as likely pathogenic (class 4) by the InSiGHT consortium based on case reports and functional analysis. The absence of multiple definitive somatic mutations in MSH2 in tumor is consistent with this variant being pathogenic. Combining all the evidence, this variant is likely pathogenic. |
| Invitae | RCV001209603 | SCV001381046 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-10-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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, 12624141, 23454724, 23729658, 28577310, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with Lynch syndrome in a family (external communication). Also, it has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 28135145, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 428464). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 692 of the MSH2 protein (p.Gly692Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. |