ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.656del (p.Pro219fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004360.5(CDH1):c.656del (p.Pro219fs)
Variation ID: 488647 Accession: VCV000488647.21
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68808816 (GRCh38) [ NCBI UCSC ] 16: 68842719 (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 Feb 8, 2018 Feb 14, 2024 Aug 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5(CDH1):c.656del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004360.5:c.656del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Pro219fs frameshift NM_001317184.2:c.656del NP_001304113.1:p.Pro219fs frameshift NM_001317185.2:c.-960del 5 prime UTR NM_001317186.2:c.-1164del 5 prime UTR NM_004360.3:c.656delC NC_000016.10:g.68808817del NC_000016.9:g.68842720del NG_008021.1:g.76526del LRG_301:g.76526del LRG_301t1:c.656del - Protein change
- P219fs
- Other names
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- Canonical SPDI
- NC_000016.10:68808815:CC:C
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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 |
4387 | 4476 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2023 | RCV000578321.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2018 | RCV000759015.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 14, 2019 | RCV001002307.9 | |
Pathogenic (1) |
reviewed by expert panel
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Aug 25, 2023 | RCV003328426.2 |
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
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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 25, 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
Accession: SCV001437604.2
First in ClinVar: Oct 10, 2020 Last updated: Sep 20, 2023 |
Comment:
The c.656del p.(Pro219fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant … (more)
The c.656del p.(Pro219fs) 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 one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760825.3). Therefore, 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. (less)
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Likely pathogenic
(Sep 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric cancer
Affected status: yes
Allele origin:
germline
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GeneID Lab - Advanced Molecular Diagnostics
Accession: SCV000680444.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Number of individuals with the variant: 1
Age: 50-59 years
Sex: female
Ethnicity/Population group: Latino
Geographic origin: United States
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Pathogenic
(Jan 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160199.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The CDH1 c.656delC; p.Pro219fs variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic/pathogenic in ClinVar (Variation ID: … (more)
The CDH1 c.656delC; p.Pro219fs variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic/pathogenic in ClinVar (Variation ID: 488647). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function CDH1 variants are considered to be pathogenic (Brooks-Wilson 2004, Guilford 1999). Based on available information, the c.656delC variant is considered to be pathogenic. REFERENCES Brooks-Wilson AR et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004 Jul;41(7):508-17. Guilford PJ et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999;14(3):249-55. (less)
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Likely pathogenic
(Mar 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888037.2
First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022 |
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Pathogenic
(May 22, 2019)
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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: SCV000760825.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro219Leufs*31) in the CDH1 gene. … (more)
This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro219Leufs*31) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 488647). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). (less)
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Pathogenic
(Jun 09, 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: SCV004045304.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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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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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 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/442ddbe1-97e7-458e-82c5-7def1bb4661a | - | - | - | - |
Text-mined citations for rs1555515284 ...
HelpRecord last updated Feb 14, 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.