ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3205G>C (p.Gly1069Arg) (rs764113705)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464681 SCV000551229 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1069 of the MSH6 protein (p.Gly1069Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs764113705, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410497). 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 RCV000483362 SCV000567409 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3205G>C at the cDNA level, p.Gly1069Arg (G1069R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly1069Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly1069Arg occurs at a position that is conserved in mammals and is located in the MutS domain (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 Gly1069Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491614 SCV000580123 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000491614 SCV000685368 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing
Counsyl RCV000662364 SCV000784751 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-02-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483362 SCV001134424 uncertain significance not provided 2019-04-21 criteria provided, single submitter clinical testing

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