ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3619C>G (p.His1207Asp) (rs760391254)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166850 SCV000217665 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000484988 SCV000566273 uncertain significance not provided 2015-04-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3619C>G at the cDNA level, p.His1207Asp (H1207D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 His1207Asp 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 Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 His1207Asp occurs at a position that is conserved across species and is not located within a known functional domain (UniProt, Kariola 2002)). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 His1207Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000629789 SCV000750745 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 1207 of the MSH6 protein (p.His1207Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs760391254, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 187154). 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"). 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.
Color RCV000166850 SCV000908424 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing

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