ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.965G>T (p.Gly322Val) (rs4987188)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131668 SCV000186696 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000203979 SCV000260822 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 322 of the MSH2 protein (p.Gly322Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs4987188, ExAC 0.008%). This variant has not been reported in the literature in individuals with an MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 142516). 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, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000410421 SCV000489132 uncertain significance Lynch syndrome I 2016-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000482522 SCV000569289 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.965G>T at the cDNA level, p.Gly322Val (G322V) 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. MSH2 Gly322Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Gly322Val is located in the Lever domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Gly322Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131668 SCV000685144 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131668 SCV000822057 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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