ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2413A>G (p.Ile805Val) (rs928923556)

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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 RCV000564287 SCV000662494 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing The p.I805V variant (also known as c.2413A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2413. The isoleucine at codon 805 is replaced by valine, 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in several other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.012 (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 Health, Inc RCV000564287 SCV000911133 likely benign Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing
Invitae RCV000815080 SCV000955523 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 805 of the MSH6 protein (p.Ile805Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 479914). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000985832 SCV001134411 uncertain significance not provided 2019-04-11 criteria provided, single submitter clinical testing

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