Submissions for variant NM_000251.3(MSH2):c.1488A>G (p.Leu496=)

gnomAD frequency: 0.00008  dbSNP: rs267607960

Total submissions: 15

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	2024-01-26	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: seen in unaffected individuals, 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 Diagnostics, LLC DBA Color Health	RCV000126812	SCV000537442	likely benign	Hereditary cancer-predisposing syndrome	2015-08-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000662437	SCV000784896	likely benign	Lynch syndrome 1	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 Laboratory Services, Illumina	RCV000662437	SCV001304350	uncertain significance	Lynch syndrome 1	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.
Sema4, Sema4	RCV000126812	SCV002528850	likely benign	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212602	SCV002552231	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662437	SCV004018387	benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
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.
Clinical Genetics, Academic Medical Center	RCV000759819	SCV001917544	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000759819	SCV001956092	likely benign	not provided		no assertion criteria provided	clinical testing