Submissions for variant NM_004360.5(CDH1):c.2292C>T (p.Asp764=)

gnomAD frequency: 0.00159  dbSNP: rs61747636

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212383	SCV000167598	benign	not specified	2013-10-30	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.
Ambry Genetics	RCV000124183	SCV000212897	benign	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197120	SCV000252792	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000197120	SCV000398581	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212383	SCV000538646	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Genetic Services Laboratory, University of Chicago	RCV000212383	SCV000593916	benign	not specified	2021-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124183	SCV000684416	likely benign	Hereditary cancer-predisposing syndrome	2015-04-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679569	SCV000806657	likely benign	not provided	2016-12-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000197120	SCV001140149	likely benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679569	SCV001472249	benign	not provided	2023-09-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679569	SCV001747765	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679569	SCV002009857	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798420	SCV002043268	benign	Breast and/or ovarian cancer	2021-07-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124183	SCV002529121	benign	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212383	SCV002551793	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	RCV000197120	SCV003926916	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1; BS2 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315848	SCV004016996	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000679569	SCV005219063	likely benign	not provided		criteria provided, single submitter	not provided
Myriad Genetics, Inc.	RCV000197120	SCV005405276	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-23	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212383	SCV000691829	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000124183	SCV000787981	likely benign	Hereditary cancer-predisposing syndrome	2017-11-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355671	SCV001550621	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Asp764= variant was identified in 1 of 68 proband chromosomes (frequency: 0.01) from individuals or families with gastric cancer (Oliveira 2002). The variant was also identified in dbSNP (rs61747636) as “with uncertain significance, other allele” and ClinVar (classified as likely benign by Ambry Genetics, Illumina, Color and 4 other submitters and as benign by Invitae, GeneDx and 1 other submitter). The variant was identified in control databases in 462 of 277,210 chromosomes at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 14 of 24,024 chromosomes (freq: 0.0006), Other in 13 of 6466 chromosomes (freq: 0.002), Latino in 56 of 34,420 chromosomes (freq: 0.002), European in 286 of 126,706 chromosomes (freq: 0.002), Ashkenazi Jewish in 8 of 10,152 chromosomes (freq: 0.0008), Finnish in 1 of 25,794 chromosomes (freq: 0.00004) and South Asian in 84 of 30,780 chromosomes (freq: 0.003), while it was not observed in the East Asian population. The variant did not have an effect on splicing as demonstrated by RT-PCR of RNA obtained from human lymphoblasts (Walsh 2011). The p.Asp764= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679569	SCV001743850	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679569	SCV001808474	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679569	SCV001924408	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679569	SCV001953369	likely benign	not provided		no assertion criteria provided	clinical testing