ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3833C>G (p.Pro1278Arg) (rs201191389)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412068 SCV000488083 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000034499 SCV000618315 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3833C>G at the cDNA level, p.Pro1278Arg (P1278R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant was observed 1/568 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). MSH6 Pro1278Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro1278Arg occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). 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 Pro1278Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000583219 SCV000690411 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV000812999 SCV000953331 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 1278 of the MSH6 protein (p.Pro1278Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 41594). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034499 SCV000043362 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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