ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2974G>A (p.Glu992Lys) (rs774755404)

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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 RCV000222273 SCV000278469 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000464929 SCV000551040 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 992 of the MSH6 protein (p.Glu992Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs774755404, ExAC 0.04%) but has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233992). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000478635 SCV000565229 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2974G>A at the cDNA level, p.Glu992Lys (E992K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu992Lys was observed at an allele frequency of 0.0435% (5/11472) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Glu992Lys occurs at a position that is not conserved and is located in domain IV 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 Glu992Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000222273 SCV000685342 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing

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