ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1877A>G (p.Gln626Arg)

dbSNP: rs1553413257
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570404 SCV000662449 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing The p.Q626R variant (also known as c.1877A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1877. The glutamine at codon 626 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration will likely impair molecular function, with a score of 0.909 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000570404 SCV001353807 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-09 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 626 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001865720 SCV002239604 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-07-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 479891). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 626 of the MSH6 protein (p.Gln626Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. 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.
All of Us Research Program, National Institutes of Health RCV004000871 SCV004835500 uncertain significance Lynch syndrome 2023-01-10 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 626 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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