ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1894A>G (p.Lys632Glu) (rs755847154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198361 SCV000254284 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 632 of the MSH6 protein (p.Lys632Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs755847154, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 216302). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Ambry Genetics RCV000213164 SCV000274700 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000411644 SCV000489236 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-09-07 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000213164 SCV000679733 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000213164 SCV000908385 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781573 SCV000919728 uncertain significance not specified 2018-01-29 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1894A>G (p.Lys632Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276694 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (1.8e-05 vs 1.40E-04), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1894A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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