ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2528G>A (p.Cys843Tyr) (rs747700106)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166329 SCV000217115 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000232782 SCV000284153 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 843 of the MSH2 protein (p.Cys843Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs747700106, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 186694). 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 tyrosine 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 RCV000166329 SCV000903536 likely benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194027 SCV001363263 uncertain significance not specified 2019-12-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2528G>A (p.Cys843Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2528G>A 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 (likely benign, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
True Health Diagnostics RCV000166329 SCV000788034 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 no assertion criteria provided clinical testing

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