ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2629G>A (p.Glu877Lys) (rs730881797)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160682 SCV000211299 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2629G>A at the cDNA level, p.Glu877Lys (E877K) 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 Glu877Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Glu877Lys occurs at a position that is not conserved and is located in MutS III domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Glu877Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000533174 SCV000624780 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 877 of the MSH6 protein (p.Glu877Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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. ClinVar contains an entry for this variant (Variation ID: 182636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color RCV000580634 SCV000685303 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing
Mendelics RCV000708877 SCV000837899 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000986724 SCV001135822 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580634 SCV001177002 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing Insufficient evidence

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