rs587781276

chr16-68823523-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004360.5(CDH1):c.2064_2065del(p.Cys688Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 7.19

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68823523-CTG-C is Pathogenic according to our data. Variant chr16-68823523-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 140781.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68823523-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2064_2065del	p.Cys688Ter	frameshift_variant	13/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1881_1882del	p.Cys627Ter	frameshift_variant	12/15
CDH1	NM_001317185.2	c.516_517del	p.Cys172Ter	frameshift_variant	13/16
CDH1	NM_001317186.2	c.99_100del	p.Cys33Ter	frameshift_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2064_2065del	p.Cys688Ter	frameshift_variant	13/16	1	NM_004360.5	P1
	ENST00000563916.1	n.2_3del		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:5 Other:1

Pathogenic, 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	Aug 01, 2022	PVS1; PS4_Supporting; PM2 (PMID: 30311375) -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	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). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	PP5, PM2_supporting, PM5_supporting, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 31, 2019	This frameshift variant causes the premature termination of CDH1 protein synthesis. In addition, it has been reported in affected families with hereditary gastric cancer in the published literature (PMIDs: 15235021 (2004), 17545690 (2007), 26072394 (2015), 29307626 (2017), and 31296550 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 16, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	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. -

CDH1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

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. -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Neoplasm of ovary;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 25, 2023

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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781276; hg19: chr16-68857426;