Submissions for variant NM_004360.5(CDH1):c.2329G>A (p.Asp777Asn)

gnomAD frequency: 0.00015  dbSNP: rs372989292

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328175	SCV001943334	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.2329G>A (p.Asp777Asn) missense variant has a frequency of 0.0001202 (34 of 282,830) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.0002400 (31 of 129,162) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149760.14, SCV000261509.8, PMIDs: 29522266, 26534844, 26976419, 25142776, 24728327). In summary, the clinical significance of this variant is classified as Likely Benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
GeneDx	RCV000487740	SCV000149760	likely benign	not provided	2020-06-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26182300, 11948460, 26534844, 26976419, 17545690, 19725995, 24728327, 25142776, 25759019, 17224074, 26580448, 27739435, 22098830, 28873162, 32426482)
Ambry Genetics	RCV000115851	SCV000186559	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	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	RCV000206674	SCV000261509	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000206674	SCV000489230	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-09-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487740	SCV000575057	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120504	SCV000600976	uncertain significance	not specified	2017-05-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115851	SCV000684423	likely benign	Hereditary cancer-predisposing syndrome	2020-05-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000206674	SCV000839095	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120504	SCV000917120	likely benign	not specified	2019-03-08	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2329G>A (p.Asp777Asn) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277184 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast and Ovarian Cancer phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2329G>A has been reported in the literature in individuals affected with cancer including breast cancer, colorectal cancer and prostate cancer (Kraus_2015, Tung_2016, Hansford_2015, Zhang_2015, Jonsson_2002). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x likely benign, 7x VUS). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000206674	SCV001775535	likely benign	Hereditary diffuse gastric adenocarcinoma	2021-02-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798345	SCV002043269	uncertain significance	Breast and/or ovarian cancer	2020-06-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120504	SCV002066855	uncertain significance	not specified	2021-02-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115851	SCV002529125	likely benign	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120504	SCV002551794	likely benign	not specified	2023-08-15	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	RCV000206674	SCV003926927	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000206674	SCV004020040	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.
PreventionGenetics, part of Exact Sciences	RCV003905101	SCV004727062	likely benign	CDH1-related condition	2023-08-21	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).
ITMI	RCV000120504	SCV000084657	not provided	not specified	2013-09-19	no assertion provided	reference population