ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.972G>A (p.Gln324=) (rs63750505)

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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 RCV000163997 SCV000214600 likely benign Hereditary cancer-predisposing syndrome 2014-07-07 criteria provided, single submitter clinical testing
Color RCV000163997 SCV000685145 benign Hereditary cancer-predisposing syndrome 2015-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000409097 SCV000487840 likely benign Lynch syndrome I 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000432873 SCV000513656 likely benign not specified 2017-12-26 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 RCV000432873 SCV000919693 benign not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.972G>A 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 observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 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 East Asian origin. The c.972G>A has been reported in the literature in individuals affected with Lynch Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.676C>T, p.R226*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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) RCV000076769 SCV000107809 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effect on splicing tested with NMD inhibitor
Invitae RCV000524427 SCV000259528 benign Hereditary nonpolyposis colon cancer 2018-01-23 criteria provided, single submitter clinical testing

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