Submissions for variant NM_004360.5(CDH1):c.2064_2065del (p.Cys688_Glu689delinsTer)

dbSNP: rs587781276

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328199	SCV001437626	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.2064_2065delTG (p.Cys688Terfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least five families meeting HDGC clinical criteria (PS4; PMID: 15235021, 17545690, 21424370, 26072394, 29307626). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4, PM5_Supporting.
Ambry Genetics	RCV000128928	SCV000172798	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	clinical testing	The c.2064_2065delTG pathogenic mutation, located in coding exon 13 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 2064 to 2065, causing a translational frameshift with a predicted alternate stop codon (p.C688*). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with CDH1-related disease (Ambry internal data). This mutation has been reported in multiple hereditary diffuse gastric cancer families (Brooks-Wilson AR et al. J. Med. Genet. 2004 Jul;41:508-17; Kaurah P et al. JAMA 2007 Jun;297:2360-72; Rogers WM et al. Am. J. Surg. Pathol. 2008 Jun;32:799-809; van der Post RS et al. Gastroenterology 2015 Oct;149(4):897-906.e19). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168178	SCV000218841	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys688*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 15235021, 17545690, 18391748). This variant is also known as c.2061delTG. ClinVar contains an entry for this variant (Variation ID: 140781). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507739	SCV000600970	pathogenic	not provided	2024-10-20	criteria provided, single submitter	clinical testing	The CDH1 c.2064_2065del (p.Cys688*) variant causes the premature termination of CDH1 protein synthesis. This variant has been reported in the published literature in individuals affected with gastric cancer (PMIDs: 15235021 (2004), 17545690 (2007), 26072394 (2015), 29307626 (2017), and 31296550 (2019)), and breast and/or ovarian cancer (PMID: 36436516 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000168178	SCV000677782	pathogenic	Hereditary diffuse gastric adenocarcinoma	2016-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128928	SCV000684393	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 13 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hereditary diffuse gastric cancer and lobular breast cancer (PMID: 15235021, 17545690, 18391748, 21424370, 26072394, 29307626, 31296550, DOI: 10.1200/po.17.00006). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168178	SCV000698377	pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-02-09	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.2064_2065delTG (p.Cys688Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent CDH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g.c.2287G>T/p.Glu763X). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple patients with HDGC or HBOC and is absent in 121404 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx	RCV000507739	SCV000779554	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing	Identified in patients with a personal or family history consistent with pathogenic variants in this gene in published literature (Brooks-Wilson 2004, Kaurah 2007, Rogers 2008, van der Post 2015, Lee 2018, Xicola 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2006).; This variant is associated with the following publications: (PMID: 15235021, 17545690, 18391748, 26072394, 31296550, 29307626, 27535533, 30730459, 21271559, 21424370)
Revvity Omics, Revvity	RCV000507739	SCV002016981	pathogenic	not provided	2019-07-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498637	SCV002810373	pathogenic	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2022-05-23	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	RCV000168178	SCV003926886	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4_Supporting; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000168178	SCV004020066	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003460879	SCV004215654	pathogenic	Familial cancer of breast	2023-08-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000507739	SCV004226787	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	PP5, PM2_supporting, PM5_supporting, PS4, PVS1
GenomeConnect - Invitae Patient Insights Network	RCV000168178	SCV001749873	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory for Genotyping Development, RIKEN	RCV003162572	SCV002758455	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003935210	SCV004750050	pathogenic	CDH1-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The CDH1 c.2064_2065delTG variant is predicted to result in premature protein termination (p.Cys688*). This variant has been reported in individuals with cleft lip and palate (Green et al 2022. PubMed ID: 36246616). Additionally, this variant has been reported in multiple individuals with diffuse gastric, breast, or colorectal cancer (see for example, Kaurah et al. 2007. PubMed ID: 17545690; Xicola et al. 2019. PubMed ID: 31296550; Stillman et al. 2022. PubMed ID: 36063148). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140781/). Nonsense variants in CDH1 are expected to be pathogenic. This variant is interpreted as pathogenic.