ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3071G>A (p.Arg1024Gln) (rs372705506)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766283 SCV000211307 uncertain significance not provided 2014-07-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3071G>A at the cDNA level, p.Arg1024Gln (R1024Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg1024Gln was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg1024Gln occurs at a position that is conserved across species and is located in the MutS domain III (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 Arg1024Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160686 SCV000214485 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000411475 SCV000488088 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-23 criteria provided, single submitter clinical testing
Invitae RCV000475900 SCV000551213 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1024 of the MSH6 protein (p.Arg1024Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs372705506, ExAC 0.002%). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182640). 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"). However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212674 SCV000601558 uncertain significance not specified 2017-03-04 criteria provided, single submitter clinical testing
Color RCV000160686 SCV000685349 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing

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