ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.874A>T (p.Thr292Ser) (rs104895022)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114837 SCV000149455 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.874A>T at the cDNA level, p.Thr292Ser (T292S) at the protein level, and results in the change of a Threonine to a Serine (ACT>TCT). This variant has been observed with allele frequency of 0.3% (2/652) in patients with the antibody deficiency syndrome IgAD and 0.1% (1/1890) in healthy controls, with no specific information about cancer history (Offer 2010). MSH2 Thr292Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH2 Thr292Ser is located in the Connector Domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Thr292Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115546 SCV000216817 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000699802 SCV000828529 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 292 of the MSH2 protein (p.Thr292Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs104895022, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 126976). 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.
Harris Lab, University of Minnesota RCV000114837 SCV000148732 not provided not provided no assertion provided not provided

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