ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.490G>T (p.Gly164Trp) (rs63750582)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767200 SCV000211210 uncertain significance not provided 2014-04-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.490G>T at the cDNA level, p.Gly164Trp (G164W) at the protein level, and results in the change of a Glycine to a Tryptophan (GGG>TGG). This variant was observed in an individual with an MSI-H, MSH2 absent colorectal cancer (Terdiman 2001). MSH2 Gly164Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Tryptophan differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. MSH2 Gly164Trp occurs at a position that is well conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Gly164Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491255 SCV000580494 pathogenic Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Well-characterized mutation at same position
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168725 SCV000592466 uncertain significance not specified 2016-10-03 criteria provided, single submitter clinical testing
Invitae RCV001060501 SCV001225194 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 164 of the MSH2 protein (p.Gly164Trp). The glycine residue is moderately 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 in individuals affected with colorectal cancer and Lynch syndrome (PMID: 11208710, 26648449). ClinVar contains an entry for this variant (Variation ID: 91110). 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.Gly164 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 1710317, 18951462, 15849733, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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