ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2857G>A (p.Glu953Lys) (rs753034685)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213285 SCV000273243 likely benign Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000485366 SCV000567152 uncertain significance not provided 2020-03-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000555735 SCV000624797 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 953 of the MSH6 protein (p.Glu953Lys). 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 (rs753034685, ExAC 0.04%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 229879). 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: Tolerated; PolyPhen-2: Possibly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781579 SCV000919738 uncertain significance not specified 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2857G>A (p.Glu953Lys) variant involves the alteration of a conserved nucleotide that is located 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 4/245082 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). Two clinical diagnostic laboratories classified this variant with conflicting interpretations, including uncertain significance and likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor 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.
Color Health, Inc RCV000213285 SCV001348346 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-13 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355880 SCV001550893 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Glu953Lys variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs753034685) as “with uncertain significance allele” and ClinVar (interpreted as "uncertain significance" by Invitae and 2 others and "likely benign" by Ambry Genetics). The variant was identified in control databases in 4 of 245,082 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5452 chromosomes (freq: 0.0002), East Asian in 3 of 17,216 chromosomes (freq: 0.0002), but was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Glu953 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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