NM_004360.5:c.2287G>T

Variant names:

• chr16-68828296-G-T
• rs587780787
• NM_004360.5:c.2287G>T

Variant summary

Our verdict is Pathogenic. The variant received 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 NM_004360.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.88
• Publications: 13 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.2287G>T	p.Glu763*	stop_gained	Exon 14 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.2104G>T	p.Glu702*	stop_gained	Exon 13 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.739G>T	p.Glu247*	stop_gained	Exon 14 of 16	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2287G>T	p.Glu763*	stop_gained	Exon 14 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.2104G>T	p.Glu702*	stop_gained	Exon 13 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.2358G>T		non_coding_transcript_exon	Exon 13 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000494 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 20, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 15, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

not provided Pathogenic:2

Jul 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDH1 c.2287G>T (p.Glu763*) variant causes the premature termination of CDH1 protein synthesis. This variant has been reported in the published literature in individuals/families affected with gastric cancer (PMIDs: 15138207 (2004), 20373070 (2010), 23752020 (2013), 29589180 (2019)) and breast cancer (PMIDs: 26270727 (2015), 28702897 (2017), 34949788 (2022)). 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.

May 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 08, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Aug 25, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Dec 25, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.9
Vest4		0.84
GERP RS		5.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

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