ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3974A>G (p.Lys1325Arg) (rs876658189)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219276 SCV000273110 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588179 SCV000568972 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3974A>G at the cDNA level, p.Lys1325Arg (K1325R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys1325Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH6 Lys1325Arg occurs at a position that is not conserved and is located in the ATPase domain and within the binding sites of MSH2 (Kariola 2002, Warren 2007, Kansikas 2011). 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 Lys1325Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000547600 SCV000624952 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1325 of the MSH6 protein (p.Lys1325Arg). The lysine residue is weakly 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 not been reported in the literature in individuals with MSH6-related disease. 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.
Integrated Genetics/Laboratory Corporation of America RCV000588179 SCV000695899 uncertain significance not provided 2016-03-07 criteria provided, single submitter clinical testing
Color RCV000219276 SCV000903217 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing

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