Submissions for variant NM_004360.5(CDH1):c.2104G>A (p.Glu702Lys)

gnomAD frequency: 0.00058  dbSNP: rs149127230

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328174	SCV000864600	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.2104G>A (p.GLu702Lys) variant has an allele frequency of 0.001714 (0.2%, 71/41,414 alleles) in the African subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1.
GeneDx	RCV000588944	SCV000149759	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26927868, 27442865, 25980754, 28135145, 28873162, 28944238, 28125075)
Ambry Genetics	RCV000115850	SCV000186220	benign	Hereditary cancer-predisposing syndrome	2019-01-17	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CSER _CC_NCGL, University of Washington	RCV000200454	SCV000212207	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2015-03-11	criteria provided, single submitter	research
Invitae	RCV000200454	SCV000253415	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212381	SCV000593913	benign	not specified	2021-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115850	SCV000684397	likely benign	Hereditary cancer-predisposing syndrome	2017-03-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212381	SCV000698378	benign	not specified	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2104G>A (p.Glu702Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 282492 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 57 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, this variant was found in nine healthy older women in a reputed germline gnomic database (FLOSSIES). The variant, c.2104G>A has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Yurgelun_2015/2017, Ghazani_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (5x) and benign (2x). Additionally, one expert panel (ClinGen CDH1 Variant Curation Expert Panel) cites this variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000200454	SCV000786546	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-05-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588944	SCV000888030	benign	not provided	2022-10-17	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196782	SCV001367415	uncertain significance	Endometrial carcinoma	2019-10-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2.
Sema4, Sema4	RCV000115850	SCV002529106	benign	Hereditary cancer-predisposing syndrome	2021-06-23	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	RCV000200454	SCV003926892	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000200454	SCV004020053	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.