ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)
Variation ID: 12241 Accession: VCV000012241.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68822081 (GRCh38) [ NCBI UCSC ] 16: 68855984 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Jun 17, 2024 Aug 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5:c.1792C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Arg598Ter nonsense NM_001317184.2:c.1609C>T NP_001304113.1:p.Arg537Ter nonsense NM_001317185.2:c.244C>T NP_001304114.1:p.Arg82Ter nonsense NM_001317186.2:c.-174C>T 5 prime UTR NC_000016.10:g.68822081C>T NC_000016.9:g.68855984C>T NG_008021.1:g.89790C>T LRG_301:g.89790C>T LRG_301t1:c.1792C>T LRG_301p1:p.Arg598Ter - Protein change
- R598*, R537*, R82*
- Other names
- NM_004360.4(CDH1):c.1792C>T
- Canonical SPDI
- NC_000016.10:68822080:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CDH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4399 | 4488 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 6, 2023 | RCV000013028.39 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2023 | RCV000213248.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000484230.12 | |
Pathogenic (1) |
reviewed by expert panel
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Aug 29, 2023 | RCV003328155.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2024 | RCV003473081.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 29, 2023)
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reviewed by expert panel
Method: curation
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CDH1-related diffuse gastric and lobular breast cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen CDH1 Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000864593.4 First in ClinVar: Jan 22, 2019 Last updated: Sep 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677742.2
First in ClinVar: Sep 26, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004701782.4
First in ClinVar: Mar 10, 2024 Last updated: Jun 17, 2024 |
Comment:
CDH1: PVS1, PM2, PP1:Moderate, PS4:Moderate, PS2:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Aug 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568308.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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 (Gayther 1998, Huntsman 2001, Humar 2002, Suriano 2005, Lynch 2008, Hakkaart 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9751616, 25525159, 23812922, 21424370, 17545690, 11419427, 11968084, 15457549, 16061854, 18442100, 20373070, 21271559, 22524656, 22225527, 21696387, 20233471, 19965908, 18788075, 29589180) (less)
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Pathogenic
(Aug 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto
Study: ERN GENTURIS
Accession: SCV003926855.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
PVS1; PS2; PS4; PM2; PP1_Strong (PMID: 30311375)
Geographic origin: Europe
Comment on evidence:
4 families fulfilling 2020 HDGC criteria-2 Familial history of gastric cancer; 2 Familial history of gastric+breast cancer
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Pathogenic
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004020069.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Apr 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469745.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV002053384.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000545422.9
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000275702.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210556.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jun 21, 2001)
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no assertion criteria provided
Method: literature only
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GASTRIC CANCER, HEREDITARY DIFFUSE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033273.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 26, 2017 |
Comment on evidence:
In a family segregating diffuse gastric cancer (HDGC; 137215), Gayther et al. (1998) found a 2095C-T transition in the CDH1 gene, resulting in an arg598-to-ter … (more)
In a family segregating diffuse gastric cancer (HDGC; 137215), Gayther et al. (1998) found a 2095C-T transition in the CDH1 gene, resulting in an arg598-to-ter (R598X) substitution. The family was subsequently studied from the point of view of genetic screening, surgical management, and pathologic findings by Huntsman et al. (2001). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978652.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553213.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979330.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. | Garcia-Pelaez J | The Lancet. Oncology | 2023 | PMID: 36436516 |
Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Māori. | Hakkaart C | Familial cancer | 2019 | PMID: 29589180 |
Comparative study of endoscopic surveillance in hereditary diffuse gastric cancer according to CDH1 mutation status. | Mi EZ | Gastrointestinal endoscopy | 2018 | PMID: 28688938 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
De novo CDH1 mutation in a family presenting with early-onset diffuse gastric cancer. | Shah MA | Clinical genetics | 2012 | PMID: 21696387 |
Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. | Xie ZM | Cancer | 2011 | PMID: 21271559 |
Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice. | Guilford P | Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association | 2010 | PMID: 20373070 |
Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer. | Pinheiro H | Human molecular genetics | 2010 | PMID: 19965908 |
Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. | Barber M | The Journal of pathology | 2008 | PMID: 18788075 |
Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. | Lynch HT | Cancer | 2008 | PMID: 18442100 |
Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. | Kaurah P | JAMA | 2007 | PMID: 17545690 |
Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. | Suriano G | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16061854 |
Genetic screening for familial gastric cancer. | Oliveira C | Hereditary cancer in clinical practice | 2004 | PMID: 20233471 |
CDH1 germline mutation in hereditary gastric carcinoma. | Wang HD | World journal of gastroenterology | 2004 | PMID: 15457549 |
Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. | Brooks-Wilson AR | Journal of medical genetics | 2004 | PMID: 15235021 |
Novel germline CDH1 mutations in hereditary diffuse gastric cancer families. | Humar B | Human mutation | 2002 | PMID: 11968084 |
Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. | Huntsman DG | The New England journal of medicine | 2001 | PMID: 11419427 |
Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. | Gayther SA | Cancer research | 1998 | PMID: 9751616 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d966550-3108-4786-8d4d-092988c239d6 | - | - | - | - |
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Text-mined citations for rs121964877 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.