ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.1493A>C (p.Asp498Ala)
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.1493A>C (p.Asp498Ala)
Variation ID: 234528 Accession: VCV000234528.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68815687 (GRCh38) [ NCBI UCSC ] 16: 68849590 (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 Mar 8, 2017 May 1, 2024 Aug 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5(CDH1):c.1493A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004360.5:c.1493A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Asp498Ala missense NM_001317184.2:c.1310A>C NP_001304113.1:p.Asp437Ala missense NM_001317185.2:c.-56A>C 5 prime UTR NM_001317186.2:c.-327A>C 5 prime UTR NC_000016.10:g.68815687A>C NC_000016.9:g.68849590A>C NG_008021.1:g.83396A>C LRG_301:g.83396A>C LRG_301t1:c.1493A>C - Protein change
- D498A, D437A
- Other names
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- Canonical SPDI
- NC_000016.10:68815686:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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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
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 7, 2019 | RCV000216744.5 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 21, 2024 | RCV000539949.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 31, 2023 | RCV000570338.11 | |
not provided (1) |
no classification provided
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- | RCV001175108.2 | |
Likely benign (1) |
reviewed by expert panel
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Aug 18, 2023 | RCV003328294.2 |
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
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
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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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Likely benign
(Aug 18, 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: SCV001365414.2 First in ClinVar: Jul 04, 2020 Last updated: Sep 20, 2023 |
Comment:
The c.1493A>C (p.Asp498Ala) variant is present at <1/100,000 alleles in the European non-Finnish subpopulation of the gnomAD cohort (1/113,758 alleles; PM2_Supporting; http://gnomad.broadinstitute.org). The variant has … (more)
The c.1493A>C (p.Asp498Ala) variant is present at <1/100,000 alleles in the European non-Finnish subpopulation of the gnomAD cohort (1/113,758 alleles; PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been seen in at least 10 individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000279435.9, SCV000637728.4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2_Supporting, BS2. (less)
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Uncertain significance
(Dec 28, 2016)
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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: SCV000279435.9
First in ClinVar: May 29, 2016 Last updated: Mar 08, 2017 |
Comment:
This variant is denoted CDH1 c.1493A>C at the cDNA level, p.Asp498Ala (D498A) at the protein level, and results in the change of an Aspartic Acid … (more)
This variant is denoted CDH1 c.1493A>C at the cDNA level, p.Asp498Ala (D498A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAC>GCC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. CDH1 Asp498Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Asp498Ala occurs at a position that is conserved across species and is located in cadherin 4 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Asp498Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Likely benign
(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: SCV003926803.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
PM2; BS2 (PMID: 30311375)
Geographic origin: Europe
Comment on evidence:
4 families not fulfilling 2020 HDGC criteria-2 Familial history of other cancers than gastric cancer or breast cancer; 1 Familial history of breast cancer; 1 … (more)
4 families not fulfilling 2020 HDGC criteria-2 Familial history of other cancers than gastric cancer or breast cancer; 1 Familial history of breast cancer; 1 Familial history of gastric+breast cancer (less)
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Uncertain significance
(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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Invitae
Accession: SCV000637728.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 498 of the CDH1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 498 of the CDH1 protein (p.Asp498Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 234528). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jun 06, 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: SCV000669006.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Feb 07, 2019)
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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: SCV001134057.2
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(Aug 31, 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: SCV000905068.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with alanine at codon 498 of the CDH1 protein. To our knowledge, functional studies have not been reported for … (more)
This missense variant replaces aspartic acid with alanine at codon 498 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several families affected with breast, gastric, and other cancers (PMID: 36436516), with one family specifying a lobular breast cancer prior to age 55. This variant has been identified in 1/251478 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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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary diffuse gastric cancer
lobular breast cancer
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - No Stomach For Cancer
Accession: SCV001338685.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab or GTR ID Peter MacCallum Cancer Centre Pathology. GenomeConnect- No Stomach for Cancer assertions … (more)
Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab or GTR ID Peter MacCallum Cancer Centre Pathology. GenomeConnect- No Stomach for Cancer assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic
Age: 30-39 years
Sex: female
Testing laboratory: Peter MacCallum Cancer Centre Pathology
Date variant was reported to submitter: 2018-11-29
Testing laboratory interpretation: Uncertain significance
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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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b16b8eee-01a1-4a10-b40c-0f1bf8dc18b7 | - | - | - | - |
Text-mined citations for rs876661065 ...
HelpRecord last updated May 01, 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.