ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2290T>G (p.Trp764Gly) (rs879254058)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236402 SCV000293323 uncertain significance not provided 2015-11-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2290T>G at the cDNA level, p.Trp764Gly (W764G) at the protein level, and results in the change of a Tryptophan to a Glycine (TGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Trp764Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Glycine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Trp764Gly occurs at a position that is conserved across species and is located in the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Trp764Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000686400 SCV000813918 uncertain significance Hereditary nonpolyposis colon cancer 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with glycine at codon 764 of the MSH2 protein (p.Trp764Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 246035). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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