Submissions for variant NM_004360.5(CDH1):c.2451G>A (p.Ala817=)

gnomAD frequency: 0.00010  dbSNP: rs149450874

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328246	SCV001142275	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.2451G>A variant is predicted silent and has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). The nucleotide is not conserved (BP7). Therefore, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP7.
Ambry Genetics	RCV000162673	SCV000213120	likely benign	Hereditary cancer-predisposing syndrome	2015-04-02	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.
Invitae	RCV000195422	SCV000253421	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195422	SCV000398583	benign	Hereditary diffuse gastric adenocarcinoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000427136	SCV000512531	benign	not specified	2015-03-30	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	RCV000162673	SCV000537464	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000195422	SCV000784766	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427136	SCV001363228	benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2451G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 277230 control chromosomes. The observed variant frequency is approximately 2.42 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 benign. To our knowledge, no occurrence of c.2451G>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant five times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000427136	SCV001469750	benign	not specified	2019-12-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798564	SCV002043275	likely benign	Breast and/or ovarian cancer	2019-11-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162673	SCV002529140	benign	Hereditary cancer-predisposing syndrome	2021-01-26	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	RCV000195422	SCV003926954	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2; BP7 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000195422	SCV004019599	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.
CeGaT Center for Human Genetics Tuebingen	RCV003422055	SCV004140035	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003937482	SCV004750058	likely benign	CDH1-related disorder	2019-03-21	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).