16-68822081-C-T

Variant names:

• chr16-68822081-C-T
• rs121964877
• NM_004360.5:c.1792C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PM5_Supporting PVS1 PM2_Supporting PS2 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID:21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID:9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID:21696387). 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, PP1_Strong, PS4, PS2, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA281000/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 5.42
• Publications: 39 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

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: 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.
• PP1: 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.1792C>T	p.Arg598*	stop_gained	Exon 12 of 16	NP_004351.1
	CDH1	NM_001317186.2		c.-174C>T		5_prime_UTR_premature_start_codon_gain	Exon 11 of 15	NP_001304115.1
	CDH1	NM_001317184.2		c.1609C>T	p.Arg537*	stop_gained	Exon 11 of 15	NP_001304113.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1792C>T	p.Arg598*	stop_gained	Exon 12 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.1609C>T	p.Arg537*	stop_gained	Exon 11 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.1863C>T		non_coding_transcript_exon	Exon 11 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Feb 02, 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 several individuals with clinical histories consistent with Hereditary Diffuse Gastric Cancer (PMID: 9751616, 11419427, 11968084, 16061854, 18442100, 29589180); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9751616, 25525159, 23812922, 21424370, 30745422, 17545690, 11419427, 11968084, 15457549, 16061854, 18442100, 20373070, 21271559, 22524656, 22225527, 20233471, 19965908, 18788075, 29589180, 21696387)

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 03, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of CDH1 protein synthesis. In addition, it has been reported in individuals and families affected with breast and/or gastric cancer in the published literature (PMID: 21696387 (2012), 21271559 (2011), 18788075 (2008), 16061854 (2005), 11419427 (2001), 9751616 (1998)). Based on the available information, this variant is classified as pathogenic.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1: PVS1, PM2, PP1:Moderate, PS4:Moderate, PS2:Supporting

Aug 26, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary diffuse gastric adenocarcinoma Pathogenic:6

Mar 07, 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.

Jun 21, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PS2; PS4; PM2; PP1_Strong (PMID: 30311375)

Sep 08, 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.Arg598*) 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 gastric and/or breast cancer (PMID: 9751616, 11419427, 16061854, 18788075, 21271559, 21696387). ClinVar contains an entry for this variant (Variation ID: 12241). For these reasons, this variant has been classified as Pathogenic.

May 15, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Arg598* variant was identified in 7 of 112 proband chromosomes (frequency: 0.06) from families with hereditary diffuse gastric cancer (Huntsman 2001, Suriano 2005, Gayther 1998, Shah 2012). The variant was identified in dbSNP (rs121964877) as “with pathogenic, uncertain significance allele”, ClinVar (classified as pathogenic by a ClinGen expert panel (2018), Invitae, Ambry Genetics, GeneDx, and two other submitters). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant was also observed in a lobular breast cancer case in an HDGC family (Suriano 2005). The c.1792C>T variant leads to a premature stop codon at position 598, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CDH1 gene are an established mechanism of disease in hereditary diffuse gastric cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 15, 2023

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 12 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 (PMID: 9751616, 11419427, 11968084, 16061854, 18788075, 19965908, 21696387, 28688938, 29589180) and lobular breast cancer (PMID: 18442100). 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.

Sep 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R598* pathogenic mutation (also known as c.1792C>T), located in coding exon 12 of the CDH1 gene, results from a C to T substitution at nucleotide position 1792. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been observed in multiple hereditary diffuse gastric cancer (HDGC) kindreds (Gayther SA et al. Cancer Res. 1998 Sep 15;58(18):4086-9; Humar B et al. Hum Mutat. 2002 May;19(5):518-25; Pinheiro H et al. Hum. Mol. Genet. 2010 Mar;19:943-52; Suriano G et al. Clin. Cancer Res. 2005 Aug;11:5401-9), including one HDGC family in which the mutation was confirmed to be de novo (Shah MA et al. Clin. Genet. 2012 Sep;82:283-7). This alteration was also identified in 4 of 94 Maori individuals from New Zealand who were diagnosed with early onset diffuse gastric cancer (Hakkaart C et al. Fam. Cancer. 2019 01;18:83-90). 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.

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

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID: 9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 21696387). 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, PP1_Strong, PS4, PS2, PM5_Supporting.

Familial cancer of breast Pathogenic:1

Feb 23, 2024

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	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.4
Vest4		0.88
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: rs121964877; hg19: chr16-68855984; COSMIC: COSV55731120; COSMIC: COSV55731120;