ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1945G>T (p.Asp649Tyr) (rs1064793188)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485501 SCV000565220 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1945G>T at the cDNA level, p.Asp649Tyr (D649Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp649Tyr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Asp649Tyr occurs at a position that is not conserved and is located within the Connector domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Asp649Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575218 SCV000669969 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000629981 SCV000750937 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 649 of the MSH6 protein (p.Asp649Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 418325). 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: "Deleterious"; PolyPhen-2: "Benign"; 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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