ClinVar Miner

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

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Total submissions: 4
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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 Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
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 colon cancer 2019-08-25 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.

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