ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.979A>G (p.Thr327Ala) (rs730881814)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160712 SCV000211343 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.979A>G at the cDNA level, p.Thr327Ala (T327A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has been reported in an individual with melanoma (Yehia 2018). MSH6 Thr327Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signal (Gassman 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 Thr327Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214500 SCV000272957 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000499861 SCV000592579 uncertain significance Lynch syndrome 2014-01-17 criteria provided, single submitter clinical testing
Invitae RCV000818095 SCV000958690 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 327 of the MSH6 protein (p.Thr327Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs730881814, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182657). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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