Submissions for variant NM_004360.5(CDH1):c.2343A>T (p.Glu781Asp)

gnomAD frequency: 0.00006  dbSNP: rs587780119

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328176	SCV001437608	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in at least 100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Although functional impact of this variant was reported from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specific variant interpretation criteria. In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
GeneDx	RCV000225693	SCV000149761	uncertain significance	not provided	2020-07-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies are conflicting; however, the ClinGen CDH1 expert group has recommended that functional studies assessing protein function not be used in CDH1 missense variant classification as they cannot confidently be used to predict pathogenicity (Kaurah 2007, Figueiredo 2013, Sanches 2014, Lee 2018); Observed in individuals with a personal or family history of gastric cancer in the literature but also in multiple individuals referred for genetic testing at GeneDx and other clinical laboratories whose clinical histories are not suggestive of hereditary diffuse gastric cancer (Kaurah 2007, Benusiglio 2013, Reuter 2018, ClinVar SCV000288464, ClinVar SCV000185618); This variant is associated with the following publications: (PMID: 19268661, 22850631, 19725995, 21271559, 26182300, 23709761, 17545690, 25388006, 22098830, 26022348, 27443514, 28301460, 29431110, 30374176)
Ambry Genetics	RCV000115852	SCV000185618	likely benign	Hereditary cancer-predisposing syndrome	2021-04-14	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	RCV000234640	SCV000288464	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000234640	SCV000489546	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-10-21	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000234640	SCV000890963	likely benign	Hereditary diffuse gastric adenocarcinoma	2020-09-09	criteria provided, single submitter	clinical testing	The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860 alleles) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). Data submitted to the ClinGen CDH1 variant curation expert panel indicates that this variant has been observed in greater than or equal to 100 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumors or lobular breast cancer and whose families do not suggest hereditary diffuse gastric cancer (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Five of seven in silico tools predict a benign effect of this variant on protein function. Functional assays have indicated mixed effects of this variant on cellular processes. This variant has been suggested to result in a reduction of binding with p120-catenin and reduced expression of E-cadherin protein encoded by CDH1 (PMIDs: 25388006, 22850631). An in vitro motility assay concluded that the E781D mutant functioned similar to a wild-type control (PMID: 19268661). As the CDH1 variant curation expert panel only approves the use of assays that measure abnormal splicing of the CDH1 gene, functional data was not applied as evidence of pathogenicity (PMID: 30311375). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 2): BS2.
Color Diagnostics, LLC DBA Color Health	RCV000115852	SCV000910792	likely benign	Hereditary cancer-predisposing syndrome	2017-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780095	SCV000917132	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2343A>T (p.Glu781Asp) results in a conservative amino acid change located in the cytoplasmic domain (IPR000233) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251468 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2343A>T has been reported in the literature in individuals with a personal or family history of diffuse gastric cancer and lobular breast cancer, and also in individuals affected with other types of cancer (e.g. Kaurah_2007, Xie_2011, Benusiglio_2013, Ring_2016, Reuter_2018, Tsai_2019, Dorling_2021) but it was also reported in unaffected individuals and families with no record of lobular breast cancer or gastric cancer (e.g. Tsai_2019, Dorling_2021). Furthermore, the ClinGen CDH1 variant curation expert panel (VCEP) reports the variant has been observed in multiple individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (Lee_2018 and ClinVar SCV001437608.1). A co-occurrence with a pathogenic variant has been reported in an endometrial cancer case (BARD1 c.1690C>T, p.Gln564X; Ring_2016). Several publications functionally evaluated the variant and its effect on cell motility, cell aggregation, cell invasion, p120 binding, EGFR activation, protein localization at the plasma membrane, and protein expression. These studies provide conflicting results, ranging from defective cell aggregation and protein localization at plasma membrane, increased cell invasion, normal cellular motility and normal EGFR activation, making interpretation of the data inconclusive (Kaurah_2007, Mateus_2009, Figueiredo_2013, Sanches_2015). In addition, the ClinGen CDH1 VCEP concluded that none of the published in vitro and in vivo functional studies could be confidently used to predict pathogenicity of E-cadherin missense variants, and therefore functional assays for missense alterations should not be used for CDH1 variant classification (except splicing assays) (Lee_2018). The following publications have been ascertained in the context of this evaluation (PMID: 23709761, 22225527, 33471991, 22850631, 26182300, 28301460, 17545690, 30311375, 30745422, 19268661, 29431110, 27443514, 25388006, 30374176, 21271559). Seven ClinVar submitters including the ClinGen CDH1 Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely benign and six ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000225693	SCV001134077	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal or family history of diffuse gastric and lobular breast cancer syndrome (DGLBCS) (PMIDs: 17545690 (2007), 23709761 (2013), 36436516 (2023)), individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 26022348 (2015), 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/)), endometrial cancer (PMID: 27443514 (2016)), as well as in unaffected controls (PMID: 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/)). Functional studies have reported that this variant may affect CDH1 protein function (PMID: 17545690 (2007), 19268661 (2009), 22850631 (2013), 25388006 (2015)), however, further research is needed. The frequency of this variant in the general population, 0.000023 (3/129176 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000225693	SCV002009856	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115852	SCV002529127	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	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	RCV000234640	SCV003926930	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000234640	SCV004020041	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492498	SCV004240429	uncertain significance	Breast and/or ovarian cancer	2022-12-21	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000234640	SCV001446373	likely benign	Hereditary diffuse gastric adenocarcinoma	2019-06-10	no assertion criteria provided	research