Submissions for variant NM_004360.5(CDH1):c.303C>T (p.Tyr101=)

gnomAD frequency: 0.00027  dbSNP: rs150789339

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162725	SCV000213191	likely benign	Hereditary cancer-predisposing syndrome	2014-10-29	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	RCV000197624	SCV000253422	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000197624	SCV000488620	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000441897	SCV000512505	benign	not specified	2015-08-27	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.
Color Diagnostics, LLC DBA Color Health	RCV000162725	SCV000684452	likely benign	Hereditary cancer-predisposing syndrome	2015-12-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001800474	SCV001471954	likely benign	not provided	2020-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000441897	SCV002041675	benign	not specified	2021-11-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000441897	SCV002047317	benign	not specified	2021-02-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162725	SCV002529167	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498805	SCV002804677	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-10-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149992	SCV003837761	likely benign	Breast and/or ovarian cancer	2021-06-24	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000197624	SCV003927015	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BP7 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315982	SCV004017013	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197624	SCV004019984	benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000441897	SCV004026628	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000197624	SCV001552497	likely benign	Hereditary diffuse gastric adenocarcinoma		no assertion criteria provided	clinical testing	The CDH1 p.Tyr101= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs150789339) as "With Likely benign allele" and ClinVar (classified as benign by GeneDx; and as likely benign by Invitae, Ambry Genetics, Counsyl and Color). The variant was identified in control databases in 21 of 276986 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 16 of 24034 chromosomes (freq: 0.0007), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 2 of 34416 chromosomes (freq: 0.000068), and European in 2 of 126494 chromosomes (freq: 0.00002), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Tyr101= 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) 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.
PreventionGenetics, part of Exact Sciences	RCV003917558	SCV004744894	likely benign	CDH1-related disorder	2019-04-24	no assertion criteria provided	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).