ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2556G>C (p.Glu852Asp) (rs587781453)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129378 SCV000184143 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410280 SCV000489475 uncertain significance Lynch syndrome I 2016-10-10 criteria provided, single submitter clinical testing
GeneDx RCV000767208 SCV000565204 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2556G>C at the cDNA level, p.Glu852Asp (E852D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu852Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MSH2 Glu852Asp occurs at a position that is conserved across species and is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Glu852Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480490 SCV000601469 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing
Invitae RCV000532767 SCV000625387 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 852 of the MSH2 protein (p.Glu852Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs587781453, 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: 141042). 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.
Integrated Genetics/Laboratory Corporation of America RCV000480490 SCV000917723 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2556G>C (p.Glu852Asp) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain 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 1.1e-05 in 277216 control chromosomes (gnomAD). 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.2556G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.
Color RCV000129378 SCV001347190 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing

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