16-68828296-G-T

Position:

• chr16-68828296-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_Supporting PVS1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2287G>T (p.Glu763Ter) variant results in a premature translational stop signal within the NMD competent region (PVS1, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in a family meeting HDGC criteria (PMID:20373070), an individual with signet ring cell carcinoma diagnosed at 33 years of age (PMID:15138207), and four individuals with DGC (2 <40 years, 2 > 40 years; PMID:29589180). These reports are mostly out of New Zealand and it is unclear if the reported individuals are all part of a larger kindred (PS4_Supporting). 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA332835/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 ENST00000261769.10 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2287G>T	p.Glu763Ter	stop_gained	14/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2104G>T	p.Glu702Ter	stop_gained	13/15		NP_001304113.1
CDH1	NM_001317185.2	c.739G>T	p.Glu247Ter	stop_gained	14/16		NP_001304114.1
CDH1	NM_001317186.2	c.322G>T	p.Glu108Ter	stop_gained	13/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2287G>T	p.Glu763Ter	stop_gained	14/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Glu763*) 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: 15138207, 20373070, 23752020). ClinVar contains an entry for this variant (Variation ID: 136065). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 15, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 04, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	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; Observed in individuals with CDH1-related phenotypes referred for genetic testing at GeneDx and in published literature (PMID: 15138207, 20373070, 23752020, 26270727, 29589180, 36246616); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22225527, 16527687, 22098830, 20373070, 24424122, 23752020, 23575477, 25525159, 26270727, 20371349, 28702897, 30977389, 30745422, 36063148, 33809393, 15138207, 34949788, 36246616, 26182300, 29589180, 37903316) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2023	The p.E763* pathogenic mutation (also known as c.2287G>T), located in coding exon 14 of the CDH1 gene, results from a G to T substitution at nucleotide position 2287. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This mutation has been reported in one individual with signet ring cell carcinoma of the stomach who was reportedly from a hereditary diffuse gastric cancer (HDGC) kindred (Charlton A et al. Gut. 2004 Jun;53(6):814-20). In a case study, this alteration was reported in two siblings, aged 38 and 32, with a strong family history of gastric cancer over at least 2 generations, including an aunt also testing positive for this mutation (Li J et al. Surg. Laparosc. Endosc. Percutan. Tech. 2013 Jun;23:e124-6). This mutation has also been reported in a cohort of 1046 individuals who were appropriate candidates for hereditary breast and ovarian cancer syndrome (HBOC) evaluation and who lacked BRCA1/2 mutations (Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). 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	Aug 01, 2022	This variant changes 1 nucleotide in exon 14 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer and lobular breast cancer in the literature (PMID: 15138207, 23575477, 29589180). 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 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.2287G>T (p.Glu763Ter) variant results in a premature translational stop signal within the NMD competent region (PVS1, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in a family meeting HDGC criteria (PMID: 20373070), an individual with signet ring cell carcinoma diagnosed at 33 years of age (PMID: 15138207), and four individuals with DGC (2 <40 years, 2 > 40 years; PMID: 29589180). These reports are mostly out of New Zealand and it is unclear if the reported individuals are all part of a larger kindred (PS4_Supporting). 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		5.3

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: rs587780787; hg19: chr16-68862199; COSMIC: COSV55733599; COSMIC: COSV55733599;