ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1189T>C (p.Tyr397His) (rs587779913)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212648 SCV000149280 uncertain significance not provided 2015-08-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1189T>C at the cDNA level, p.Tyr397His (Y397H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a gastric adenocarcinoma (COSMIC). MSH6 Tyr397His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Tyr397His occurs at a position that is not conserved and is located within the MutS domain I and MSH2 binding site (Kariola 2002, Terui 2013). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider MSH6 Tyr397His to be a variant of uncertain significance.
Ambry Genetics RCV000115371 SCV000186264 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000457819 SCV000551082 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 397 of the MSH6 protein (p.Tyr397His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127557). 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 histidine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000115371 SCV000911826 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing

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