ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.190G>A (p.Ala64Thr) (rs587779921)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128983 SCV000172871 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000531333 SCV000624702 uncertain significance Hereditary nonpolyposis colon cancer 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 64 of the MSH6 protein (p.Ala64Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 140804). 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 threonine 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, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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