ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.114C>G (p.Asp38Glu) (rs587779074)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164456 SCV000215099 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524331 SCV000254378 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 38 of the MSH2 protein (p.Asp38Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs587779074, ExAC 0.03%). This variant has been reported in an individual affected with colon cancer (PMID: 18446350), an individual with suspected Lynch syndrome (PMID: 25980754), and a family affected with Lynch syndrome (PMID: 15943554). However, in that family a pathogenic variant was also identified in MSH2 in the two affected siblings (PMID: 15943554). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.114C>G variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90555). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000662913 SCV000785848 uncertain significance Lynch syndrome I 2017-12-27 criteria provided, single submitter clinical testing
Color RCV000164456 SCV000908267 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780454 SCV000917716 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: MSH2 c.114C>G (p.Asp38Glu) results in a conservative amino acid change located in the DNA mismatch repair ATPase domain 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 2.4e-05 in 253244 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in individuals affected with Lynch Syndrome (Grabowski_2005, Urso_2008, Yurgelun_2015). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 Del exons 3-5, in-frame deletion), however no clinical information and/or phase of two variants were provided by authors to rule out deleterious effect of c.114C>G (Grabowski_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.