ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2770A>T (p.Thr924Ser) (rs758873844)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218606 SCV000273213 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000486781 SCV000572236 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2770A>T at the cDNA level, p.Thr924Ser (T924S) at the protein level, and results in the change of a Threonine to a Serine (ACT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign germline variant. MSH6 Thr924Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Thr924Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000218606 SCV000685322 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-09 criteria provided, single submitter clinical testing
Invitae RCV000629928 SCV000750884 uncertain significance Hereditary nonpolyposis colon cancer 2017-12-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 924 of the MSH6 protein (p.Thr924Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs758873844, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 229859). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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