Submissions for variant NM_004360.5(CDH1):c.1138-3C>T

gnomAD frequency: 0.00042  dbSNP: rs36103202

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328248	SCV000864606	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-24	reviewed by expert panel	curation	The c.1138-3C>T variant has an allele frequency of 0.00121 (0.121%, 29/24,036 alleles) in the African subpopulation of the gnomAD cohort (BS1). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BP4 (Variant Interpretation Guidelines Version 3.1).
Ambry Genetics	RCV000163579	SCV000214138	likely benign	Hereditary cancer-predisposing syndrome	2018-11-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000200649	SCV000252788	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000248533	SCV000310120	benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000200649	SCV000488641	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000759722	SCV000518175	likely benign	not provided	2020-08-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27978560, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000163579	SCV000684330	likely benign	Hereditary cancer-predisposing syndrome	2015-10-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759722	SCV000889239	benign	not provided	2023-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000248533	SCV000917114	benign	not specified	2017-10-31	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1138-3C>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 36/277198 control chromosomes from all ethnicities, but was predominantly observed in the African subpopulation at a frequency of 0.001207 (29/24036). This frequency is about 43 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign or likely benign. Taken together, this variant is classified as benign.
Sema4, Sema4	RCV000163579	SCV002531140	likely benign	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000200649	SCV003926744	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1; BP4 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316001	SCV004017024	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200649	SCV004019992	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.