ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.2644G>A (p.Asp882Asn)
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.
Uncertain significance(10); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004360.5(CDH1):c.2644G>A (p.Asp882Asn)
Variation ID: 127929 Accession: VCV000127929.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68833494 (GRCh38) [ NCBI UCSC ] 16: 68867397 (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 Jun 1, 2016 Sep 16, 2024 Mar 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5:c.2644G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Asp882Asn missense NM_001317184.2:c.2461G>A NP_001304113.1:p.Asp821Asn missense NM_001317185.2:c.1096G>A NP_001304114.1:p.Asp366Asn missense NM_001317186.2:c.679G>A NP_001304115.1:p.Asp227Asn missense NC_000016.10:g.68833494G>A NC_000016.9:g.68867397G>A NG_008021.1:g.101203G>A LRG_301:g.101203G>A LRG_301t1:c.2644G>A - Protein change
- D882N, D821N, D227N, D366N
- Other names
- p.D882N:GAC>AAC
- Canonical SPDI
- NC_000016.10:68833493:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00009
Exome Aggregation Consortium (ExAC) 0.00003
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
4445 | 4538 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2023 | RCV000115860.16 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2024 | RCV000212394.12 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 21, 2024 | RCV000232913.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV002465518.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 2, 2023 | RCV003460831.1 | |
CDH1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2023 | RCV003398713.4 |
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
Help
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
Help
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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Uncertain significance
(Jul 20, 2021)
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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: SCV001469751.2
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 03, 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: SCV000689523.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with asparagine at codon 882 of the CDH1 protein. To our knowledge, functional studies have not been reported for … (more)
This missense variant replaces aspartic acid with asparagine at codon 882 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with breast cancer, but also in unaffected individuals in the literature (PMID: 30287823, 30306255, 33471991). This variant has been identified in 15/282744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric adenocarcinoma
Affected status: no
Allele origin:
germline
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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001424797.1 First in ClinVar: Jul 29, 2020 Last updated: Jul 29, 2020 |
Comment:
To our knowledge, this sequence variant has not been previously reported in the literature. The p.Asp882Asn variant has an overall allele frequency of 0.00005305 in … (more)
To our knowledge, this sequence variant has not been previously reported in the literature. The p.Asp882Asn variant has an overall allele frequency of 0.00005305 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may have a deleterious effect due to its relative conservation and predicted impact on the final protein product. It is unknown at this time whether this variant increases cancer risk; therefore, we consider it to be a variant of uncertain significance (VUS). (less)
Indication for testing: family history of breast and ovarian cancer
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Uncertain significance
(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: no
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: SCV003926975.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Not applicable criteria (PMID: 30311375)
Geographic origin: Europe
Comment on evidence:
2 families not fulfilling 2020 HDGC criteria-2 Familial history of breast cancer
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Uncertain significance
(Sep 02, 2023)
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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: SCV004215652.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Mar 27, 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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GeneDx
Accession: SCV000149769.16
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Reported in the literature in individuals with personal or family history of breast cancer and also in unaffected control(s) (PMID: 30306255, 30287823, 33471991, 36436516); In … (more)
Reported in the literature in individuals with personal or family history of breast cancer and also in unaffected control(s) (PMID: 30306255, 30287823, 33471991, 36436516); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29338689, 15235021, 22850631, 36243179, 33471991, 30287823, 30306255, 36436516) (less)
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Uncertain significance
(Aug 05, 2020)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714552.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760871.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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CDH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104552.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CDH1 c.2644G>A variant is predicted to result in the amino acid substitution p.Asp882Asn. This variant has been reported with uncertain significance in an individual … (more)
The CDH1 c.2644G>A variant is predicted to result in the amino acid substitution p.Asp882Asn. This variant has been reported with uncertain significance in an individual with breast/ovarian cancer (Bonache et al. 2018. PubMed ID: 30306255). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68867397-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Jan 21, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000288478.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Uncertain significance
(Aug 03, 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: SCV000184064.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.D882N variant (also known as c.2644G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide … (more)
The p.D882N variant (also known as c.2644G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2644. The aspartic acid at codon 882 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in an individual with ductal carcinoma in situ diagnosed at age 29 with a family history of diffuse gastric cancer diagnosed at age 52 in a maternal cousin (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). This alteration has also been reported in breast cancer cases, as well as in controls (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Variants of cancer susceptibility genes in Korean BRCA1/2 mutation-negative patients with high risk for hereditary breast cancer. | Park JS | BMC cancer | 2018 | PMID: 29338689 |
Text-mined citations for rs200104963 ...
HelpRecord last updated Sep 29, 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.