ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2604G>A (p.Met868Ile) (rs749508276)

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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 RCV000570721 SCV000662518 likely benign Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000588628 SCV000695819 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2604G>A (p.Met868Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution 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 the large control database ExAC at a frequency of 0.0000083 (1/120240 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been 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 RCV000692110 SCV000819918 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 868 of the MSH6 protein (p.Met868Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs749508276, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 479929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000570721 SCV000911256 likely benign Hereditary cancer-predisposing syndrome 2016-12-15 criteria provided, single submitter clinical testing

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