ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2162G>T (p.Arg721Ile) (rs876660319)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222450 SCV000277648 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000483504 SCV000568680 uncertain significance not provided 2016-08-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2162G>T at the cDNA level, p.Arg721Ile (R721I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg721Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg721Ile occurs at a position that is not conserved and is located in the MutS III domain (Terui 2013). 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 Arg721Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000538892 SCV000624730 uncertain significance Hereditary nonpolyposis colon cancer 2017-07-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 721 of the MSH6 protein (p.Arg721Ile). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and isoleucine. 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: 233301). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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