ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2074G>T (p.Gly692Trp) (rs63750232)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000490880 SCV000580439 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing The p.G692W variant (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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659883 SCV000781775 uncertain significance Lynch syndrome I 2016-11-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington 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 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. This variant is not present in population databases (ExAC no frequency). 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). 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 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. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.