ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3949C>G (p.His1317Asp) (rs759092293)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463911 SCV000551160 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 1317 of the MSH6 protein (p.His1317Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. The frequency data for this variant in the population databases is considered 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 MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410463). 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: "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.
GeneDx RCV000485411 SCV000565240 uncertain significance not provided 2015-02-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3949C>G at the cDNA level, p.His1317Asp (H1317D) 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 His1317Asp 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 His1317Asp occurs at a position that is conserved across species and is located in the MutS domain V (Terui 2013). 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 His1317Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566983 SCV000662360 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662834 SCV000785692 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-11-01 criteria provided, single submitter clinical testing
Color RCV000566983 SCV000904027 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing

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