Submissions for variant NM_000251.3(MSH2):c.2271C>T (p.Tyr757=)

gnomAD frequency: 0.00006  dbSNP: rs56076152

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163040	SCV000213530	likely benign	Hereditary cancer-predisposing syndrome	2014-11-07	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	RCV001080852	SCV000253154	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163040	SCV000685029	likely benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759113	SCV000888219	benign	not provided	2022-11-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140259	SCV001300498	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358733	SCV001554578	likely benign	not specified	2021-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000759113	SCV001889241	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798566	SCV002042101	likely benign	Breast and/or ovarian cancer	2022-11-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001358733	SCV002071892	likely benign	not specified	2021-09-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163040	SCV002534464	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004535062	SCV004715807	likely benign	MSH2-related disorder	2024-01-16	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	RCV003995227	SCV004825836	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357863	SCV001553454	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Tyr757= variant was not identified in the literature nor was it identified in the COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs56076152) as "With Likely benign allele", ClinVar (classified as likely benign by Ambry Genetics, Invitae, Color Genomics), and in UMD-LSDB (1x as unclassified variant), databases. The variant was identified in control databases in 30 of 277180 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 2 of 34420 chromosomes (freq: 0.00006), European in 6 of 126688 chromosomes (freq: 0.000047), Ashkenazi Jewish in 6 of 10152 chromosomes (freq: 0.00059), East Asian in 11 of 18870 chromosomes (freq: 0.00058), while the variant was not observed in the Finnish, and South Asian populations. The p.Tyr757= 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.