ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3062C>G (p.Ala1021Gly) (rs63750287)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767078 SCV000565991 uncertain significance not provided 2015-03-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3062C>G at the cDNA level, p.Ala1021Gly (A1021G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has been identified in tumor tissue from an individual with brain cancer (Nguyen 2014). MSH6 Ala1021Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala1021Gly occurs at a position that is conserved in mammals and is located in domain III of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Ala1021Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480054 SCV000601557 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565319 SCV000662477 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000565319 SCV000685347 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing
Invitae RCV000706203 SCV000835241 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 1021 of the MSH6 protein (p.Ala1021Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs63750287, 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: 418722). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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