ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2419G>A (p.Glu807Lys) (rs587779923)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656895 SCV000149299 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2419G>A at the cDNA level, p.Glu807Lys (E807K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been observed in an individual with early-onset colorectal cancer, in an individual with glioblastoma multiforme, and in an individual with early-onset breast cancer, who also carried a pathogenic BRCA1 variant (Lu 2015, Cock-Rada 2017, DeRycke 2017). MSH6 Glu807Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Glu807Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000199520 SCV000254296 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 807 of the MSH6 protein (p.Glu807Lys). 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 (rs587779923, ExAC 0.002%). This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127570). 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. 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.
Counsyl RCV000409470 SCV000488055 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491756 SCV000580212 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115390 SCV000601532 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Color RCV000491756 SCV000685285 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656895 SCV000805867 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing
Mendelics RCV000708875 SCV000837897 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765687 SCV000897029 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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