Submissions for variant NM_000251.3(MSH2):c.1563T>C (p.Tyr521=)

gnomAD frequency: 0.00053  dbSNP: rs63750330

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212604	SCV000170340	benign	not specified	2014-01-13	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	RCV000126814	SCV000212868	likely benign	Hereditary cancer-predisposing syndrome	2014-06-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524348	SCV000252653	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409514	SCV000489655	likely benign	Lynch syndrome 1	2016-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212604	SCV000595829	likely benign	not specified	2016-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126814	SCV000689996	likely benign	Hereditary cancer-predisposing syndrome	2015-08-10	criteria provided, single submitter	clinical testing
Mendelics	RCV003323289	SCV000837833	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092632	SCV001249233	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000409514	SCV001297153	uncertain significance	Lynch syndrome 1	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000126814	SCV002534380	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212604	SCV002552235	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149746	SCV003838303	likely benign	Breast and/or ovarian cancer	2022-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126814	SCV004014998	benign	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409514	SCV004018364	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.
All of Us Research Program, National Institutes of Health	RCV003997150	SCV004831702	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354893	SCV001549613	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Tyr521Tyr variant was identified in 3 of 4080 proband chromosomes (frequency: 0.0007) from individuals or families with ovarian cancer or Lynch related colon cancer (Kurzawski_2002_12362047, Kurzawski_2002_11879922, Pal_2012_23047549). The variant was also identified in the following databases: dbSNP (ID: rs63750330) as With “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 3x as likely benign by Ambry Genetics, Counsyl, University of Chicago, 1x as uncertain significance by InSight), Clinvitae (4x by ClinVar), UMD-LSDB (1x as UV), Insight Colon Cancer Gene Variant Database (1x), Mismatch Repair Genes Variant Database and Insight Hereditary Tumors Database (6x reported as Class 3). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer databases. The variant was identified in control databases in 121 of 277184 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 3 of 6462 chromosomes (freq: 0.0005), European Non-Finnish in 81 of 126680 chromosomes (freq: 0.0006), Ashkenazi Jewish in 3 of 10150 chromosomes (freq: 0.0003), European Finnish in 34 of 25794 chromosomes (freq: 0.0013), while the variant was not observed in the African, Latino, East Asian, and South Asian populations. The p.Tyr521Tyr 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.