ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.214G>A (p.Asp72Asn)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004360.5(CDH1):c.214G>A (p.Asp72Asn)
Variation ID: 136064 Accession: VCV000136064.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68801720 (GRCh38) [ NCBI UCSC ] 16: 68835623 (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 Jul 1, 2016 May 1, 2024 Aug 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5:c.214G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Asp72Asn missense NM_001317184.2:c.214G>A NP_001304113.1:p.Asp72Asn missense NM_001317185.2:c.-1402G>A 5 prime UTR NM_001317186.2:c.-1606G>A 5 prime UTR NC_000016.10:g.68801720G>A NC_000016.9:g.68835623G>A NG_008021.1:g.69429G>A LRG_301:g.69429G>A LRG_301t1:c.214G>A P12830:p.Asp72Asn - Protein change
- D72N
- Other names
- p.D72N:GAC>AAC
- NM_004360.5(CDH1):c.214G>A
- Canonical SPDI
- NC_000016.10:68801719: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 |
4445 | 4538 |
Conditions - Germline
Condition
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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
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 26, 2021 | RCV000131154.14 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000123243.24 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000235149.8 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 9, 2023 | RCV000656818.13 | |
Likely benign (1) |
reviewed by expert panel
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Aug 3, 2023 | RCV003328194.1 |
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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Likely benign
(Aug 03, 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: SCV004035095.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
The c.214G>A (p.Asp72Asn) missense variant has a maximum subpopulation frequency of 0.048% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over … (more)
The c.214G>A (p.Asp72Asn) missense variant has a maximum subpopulation frequency of 0.048% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 300 probands not meeting HDGC phenotype criteria (BS2; SCV000210893.13, SCV000186096.8, SCV000166549.12). 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: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) (less)
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Likely benign
(Feb 25, 2021)
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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: SCV000210893.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with lung cancer and in 1/11,241 controls but … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with lung cancer and in 1/11,241 controls but not in the associated breast cancer cases (Momozawa 2018, Santeufemia 2019); This variant is associated with the following publications: (PMID: 30287823, 30979070, 31159747, 31784482) (less)
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Uncertain significance
(Mar 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019999.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Likely benign
(Jan 22, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919098.2
First in ClinVar: Jun 02, 2019 Last updated: Mar 30, 2024 |
Comment:
Variant summary: CDH1 c.214G>A (p.Asp72Asn) results in a conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Three of … (more)
Variant summary: CDH1 c.214G>A (p.Asp72Asn) results in a conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 1607036 control chromosomes, predominantly at a frequency of 0.00045 within the Latino subpopulation in the gnomAD database (v4 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.214G>A, has been reported in the literature in individuals affected with breast cancer (Tsaousis_2019, Dorling_2021), but it was also found in several controls (Momozawa_2018, Dorling_2021, Okawa_2023). In addition, this variant was also reported in 3/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: NO_PMID, 19011631, 30287823, 31159747, 33471991, 36243179). ClinVar contains an entry for this variant (Variation ID: 136064). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Dec 09, 2019)
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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: SCV000186096.9
First in ClinVar: Aug 06, 2014 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
(May 12, 2017)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806654.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821970.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Likely benign
(Jul 24, 2015)
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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: SCV000902795.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Feb 12, 2016)
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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: SCV000488289.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Likely benign
(Jan 09, 2023)
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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: SCV000600973.3
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
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Likely benign
(Jan 29, 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: SCV000166549.13
First in ClinVar: Jun 16, 2014 Last updated: Feb 14, 2024 |
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Likely benign
(Jul 26, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529109.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary diffuse gastric cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839074.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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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: SCV003927004.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
BS2_Supporting (PMID: 30311375)
Geographic origin: Europe
Comment on evidence:
3 families not fulfilling 2020 HDGC criteria-2 Familial history of breast cancer; 1 Familial history of gastric+breast cancer
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV001550075.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CDH1 p.Asp72Asn variant was not identified in 14102 proband chromosomes from individuals or families with breast cancer but was present in 4 of 22482 … (more)
The CDH1 p.Asp72Asn variant was not identified in 14102 proband chromosomes from individuals or families with breast cancer but was present in 4 of 22482 control chromosomes (frequency: 0.0009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs35606263) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and five other submitters), and LOVD 3.0 (2x as VUS). The variant was identified in control databases in 29 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24020 chromosomes (freq: 0.0001), Latino in 17 of 34418 chromosomes (freq: 0.0005), European in 6 of 126588 chromosomes (freq: 0.00005), Ashkenazi Jewish in 3 of 10148 chromosomes (freq: 0.0003); it was not observed in the Other, East Asian, Finnish, or South Asian populations. The p.Asp72 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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 |
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
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 |
Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel. | Lerner-Ellis J | Journal of medical genetics | 2020 | PMID: 31784482 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. | COGENT Study | Nature genetics | 2008 | PMID: 19011631 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/302f2528-fb93-4046-8918-31d40168855a | - | - | - | - |
Text-mined citations for rs35606263 ...
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.