ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3104G>A (p.Arg1035Gln) (rs730881801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196222 SCV000254303 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1035 of the MSH6 protein (p.Arg1035Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs730881801, 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: 216311). 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.
GeneDx RCV000759859 SCV000567271 uncertain significance not provided 2016-05-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3104G>A at the cDNA level, p.Arg1035Gln (R1035Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in an individual with prostate cancer (Lu 2015). MSH6 Arg1035Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg1035Gln occurs at a position that is conserved across species and is located within the MutS domain III (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg1035Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568269 SCV000676117 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759859 SCV000889481 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing
Color RCV000568269 SCV000906514 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-21 criteria provided, single submitter clinical testing

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