ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.95G>T (p.Gly32Val) (rs771426932)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487312 SCV000565206 uncertain significance not provided 2014-10-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.95G>T at the cDNA level, p.Gly32Val (G32V) at the protein level, and results in the change of a Glycine to a Valine (GGC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly32Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Gly32Val occurs at a position that is poorly conserved across species and is not located in a known functional domain (Kariola 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Gly32Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566154 SCV000662497 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000630215 SCV000751171 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 32 of the MSH6 protein (p.Gly32Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been observed in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 418317). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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