ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2195G>A (p.Arg732Gln) (rs749746725)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223534 SCV000279763 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2195G>A at the cDNA level, p.Arg732Gln (R732Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature a germline variant; however, it has been reported as a somatic variant in a colorectal tumor (Vasovcak 2012). MSH6 Arg732Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg732Gln occurs at a position that is conserved across species and is located in the lever domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg732Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000532996 SCV000624733 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 732 of the MSH6 protein (p.Arg732Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs749746725, ExAC 0.006%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234747). 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.
Ambry Genetics RCV000564357 SCV000662445 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000564357 SCV000685264 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000758666 SCV000887437 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.2195G>A has a 34.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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