ClinVar Miner

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

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Total submissions: 10
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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 colorectal neoplasms 2020-12-03 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 This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc 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 2020-07-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000759819 SCV001551079 likely benign not provided no assertion criteria provided clinical testing The MSH2 p.Leu496= variant was identified in the literature to have no effect on splicing using a functional assay of exon inclusion in which patient mutant and wildtype genomic DNA was inserted into a splicing reporter minigene assay (Tournier_2008_18561205). The variant was identified in dbSNP (ID: rs267607960) “With Likely benign allele”, ClinVar (classified likely benign, reviewed by an expert panel (2013); submitters: benign by Invitae and GeneDx, and likely benign by InSIGHT, Ambry Genetics and Color Genomics Inc.), Clinvitae (3x), UMD-LSDB (2x as neutral), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (8x as class2), and in control databases in 33 of 277114 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24030 chromosomes (freq: 0.00008), “Other” in 1 of 6460 chromosomes (freq: 0.0002), Latino in 3 of 34416 chromosomes (freq: 0.00009), European Non-Finnish in 27 of 126618 chromosomes (freq: 0.0002); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was not identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The p.Leu496= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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