ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2154A>G (p.Gln718=) (rs63750810)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076412 SCV000107441 likely benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Synonymous substitution with no effect on splicing tested with NMD inhibitor.
GeneDx RCV000212616 SCV000170346 benign not specified 2014-02-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000126820 SCV000212749 likely benign Hereditary cancer-predisposing syndrome 2014-10-14 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign;In silico models in agreement (benign)
Invitae RCV001080051 SCV000252655 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000126820 SCV000685016 benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679304 SCV000806026 likely benign not provided 2017-03-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212616 SCV000917721 benign not specified 2018-12-07 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2154A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 277216 control chromosomes, predominantly at a frequency of 0.00067 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2154A>G has been reported in the literature in individuals affected with Lynch Syndrome (Mangold_2005, Renkonen_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additonally, one publication reports the variant to co-occur with a pathogenic variant, further evidence for the benign nature of this variant (Mangold_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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000986682 SCV001135751 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986682 SCV001300495 uncertain significance Lynch syndrome I 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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.