ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1488A>G (p.Leu496=) (rs267607960)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076175 SCV000107191 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effect on splicing, tested with NMD inhibitor
Invitae RCV001082265 SCV000166263 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000212602 SCV000170338 benign not specified 2014-04-15 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 RCV000126812 SCV000214596 likely benign Hereditary cancer-predisposing syndrome 2014-11-21 criteria provided, single submitter clinical testing
Color RCV000126812 SCV000537442 likely benign Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing
Counsyl RCV000662437 SCV000784896 likely benign Lynch syndrome I 2017-02-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759819 SCV000889414 likely benign not provided 2017-08-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212602 SCV000919712 likely benign not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1488A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing, which has been confirmed by an ex vivo splicing assay (Tournier_2008). The variant allele was found at a frequency of 0.00012 in 277114 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00012 vs 0.00057), allowing no conclusion about variant significance. c.1488A>G has been reported in the literature in individuals affected with sporadic renal cell carcinoma or epithelial ovarian cancer. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000662437 SCV001304350 uncertain significance Lynch syndrome I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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