ClinVar Miner

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

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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 RCV000126820 SCV000212749 likely benign Hereditary cancer-predisposing syndrome 2014-10-14 criteria provided, single submitter clinical testing
Color RCV000126820 SCV000685016 benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing
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.
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.
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.
Invitae RCV000524378 SCV000252655 benign Hereditary nonpolyposis colon cancer 2018-01-03 criteria provided, single submitter clinical testing
PreventionGenetics RCV000679304 SCV000806026 likely benign not provided 2017-03-22 criteria provided, single submitter clinical testing

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