Submissions for variant NM_000251.3(MSH2):c.198C>T (p.Tyr66=)

gnomAD frequency: 0.00011  dbSNP: rs730881784

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212580	SCV000211255	benign	not specified	2014-07-28	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	RCV000160652	SCV000212860	likely benign	Hereditary cancer-predisposing syndrome	2014-10-24	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.
Invitae	RCV000206199	SCV000260791	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409186	SCV000489340	likely benign	Lynch syndrome 1	2016-09-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160652	SCV000537504	likely benign	Hereditary cancer-predisposing syndrome	2015-11-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409186	SCV001304221	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284171	SCV001469806	likely benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212580	SCV002066720	likely benign	not specified	2020-12-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160652	SCV002534435	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212580	SCV002552187	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409186	SCV004018293	benign	Lynch syndrome 1	2023-03-20	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492655	SCV004239277	likely benign	Breast and/or ovarian cancer	2022-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212580	SCV004241702	likely benign	not specified	2023-12-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544470	SCV004776793	likely benign	MSH2-related disorder	2021-04-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003998489	SCV004832027	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354005	SCV000592454	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	MSH2, EXON01, c.198C>T, p.= (p.Tyr66Tyr), Heterozygous, Likely benign rnrnThe MSH2 c.198C>T variant was not identified in the literature nor was it identified in the COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD) and GeneInsight - COGR database. The variant was identified in dbSNP (ID: rs730881784) as “With Likely benign allele”, ClinVar database (classified as benign by GeneDx and likely benign by Ambry Genetics and Invitae) and UMD (1x with an “unclassified variant” classification). This variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 11 of 83058 chromosomes (freq. 0.0001) in the following populations: European in 11 of 47956 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Tyr66Tyr 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. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.