ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1661G>A (p.Arg554His) (rs730881791)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767214 SCV000211278 uncertain significance not provided 2016-09-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1661G>A at the cDNA level, p.Arg554His (R554H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg554His 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 Histidine share similar properties, this is considered a conservative amino acid substitution. MSH6 Arg554His occurs at a position that is not conserved and is located within the MSH2 binding site and the MutS binding domain II (Kariola 2002, 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 Arg554His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160668 SCV000601512 uncertain significance not specified 2017-03-21 criteria provided, single submitter clinical testing
Invitae RCV000560061 SCV000624677 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 554 of the MSH6 protein (p.Arg554His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs730881791, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182623). 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: "Tolerated"; 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.
Ambry Genetics RCV000571101 SCV000669891 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571101 SCV000690215 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Mendelics RCV000708869 SCV000837884 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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