ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1793A>G (p.Lys598Arg) (rs587779919)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759845 SCV000149293 uncertain significance not provided 2016-08-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1793A>G at the cDNA level, p.Lys598Arg (K598R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has been observed in at least one individual with breast cancer (Tung 2016). MSH6 Lys598Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH6 Lys598Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in domain II of the MutS 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 Lys598Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168326 SCV000219013 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 598 of the MSH6 protein (p.Lys598Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 127565). 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 arginine 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. 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.
Genetic Services Laboratory, University of Chicago RCV000115384 SCV000595858 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115384 SCV000601517 uncertain significance not specified 2017-07-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565738 SCV000662354 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Counsyl RCV000663315 SCV000786584 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-05-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759845 SCV000889460 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing
Color RCV000565738 SCV000911465 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 criteria provided, single submitter clinical testing

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