ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2857G>A (p.Glu953Lys) (rs753034685)

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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 RCV000213285 SCV000273243 likely benign Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
GeneDx RCV000485366 SCV000567152 uncertain significance not provided 2016-09-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2857G>A at the cDNA level, p.Glu953Lys (E953K) 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 Glu953Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Glu953Lys occurs at a position that is not conserved and is located within 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 Glu953Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781579 SCV000919738 uncertain significance not specified 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2857G>A (p.Glu953Lys) variant involves the alteration of a conserved nucleotide that is located in the DNA mismatch repair protein MutS core domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/245082 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). Two clinical diagnostic laboratories classified this variant with conflicting interpretations, including uncertain significance and likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000555735 SCV000624797 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 953 of the MSH6 protein (p.Glu953Lys). 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 (rs753034685, ExAC 0.04%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 229879). 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 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.

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