ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3586G>C (p.Glu1196Gln) (rs75095286)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467878 SCV000551255 uncertain significance Hereditary nonpolyposis colon cancer 2017-12-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1196 of the MSH6 protein (p.Glu1196Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs75095286, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410511). 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 disruptive, 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.
Ambry Genetics RCV000574327 SCV000662476 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000574327 SCV000685417 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587963 SCV000695876 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3586G>C (p.Glu1196Gln) variant located in the P-loop containing nucleoside triphosphate hydrolase domain (via InterPro) causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121274 (1/60637), predominantly in the African cohort, 2/10370 (1/5185), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (0.0001421). The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, due to the limited available information (ie, lack of clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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