ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.164T>G (p.Val55Gly)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004360.5(CDH1):c.164T>G (p.Val55Gly)
Variation ID: 132769 Accession: VCV000132769.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 68801670 (GRCh38) [ NCBI UCSC ] 16: 68835573 (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 9, 2014 May 1, 2024 Aug 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004360.5:c.164T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Val55Gly missense NM_001317184.2:c.164T>G NP_001304113.1:p.Val55Gly missense NM_001317185.2:c.-1452T>G 5 prime UTR NM_001317186.2:c.-1656T>G 5 prime UTR NC_000016.10:g.68801670T>G NC_000016.9:g.68835573T>G NG_008021.1:g.69379T>G LRG_301:g.69379T>G LRG_301t1:c.164T>G - Protein change
- V55G
- Other names
- NM_004360.5(CDH1):c.164T>G
- p.Val55Gly
- Canonical SPDI
- NC_000016.10:68801669:T:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
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 |
4447 | 4540 |
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
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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
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000119234.25 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000120511.14 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 21, 2022 | RCV000131233.17 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 1, 2022 | RCV000656817.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 25, 2023 | RCV003492514.1 | |
Likely benign (1) |
reviewed by expert panel
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Aug 17, 2023 | RCV003328184.2 | |
CDH1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Apr 7, 2023 | RCV003390803.4 |
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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Likely benign
(Aug 17, 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: SCV001943346.2 First in ClinVar: Sep 29, 2021 Last updated: Sep 20, 2023 |
Comment:
The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer … (more)
The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. (less)
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Uncertain significance
(Jan 28, 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: SCV001134062.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 26, 2021 |
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Uncertain significance
(Dec 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069928.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(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: SCV002760848.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Apr 07, 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: SCV004120322.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CDH1 c.164T>G variant is predicted to result in the amino acid substitution p.Val55Gly. This variant has been reported in an individual with colorectal cancer … (more)
The CDH1 c.164T>G variant is predicted to result in the amino acid substitution p.Val55Gly. This variant has been reported in an individual with colorectal cancer that harbored a pathogenic MUTYH variant (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). It has been reported in an individual with breast cancer that harbored variants in other genes (Table S2, Wen et al. 2014. PubMed ID: 24969172). It has been reported in an individual with recurrent pregnancy loss (Tables 1 and 2, Quintero-Ronderos et al. 2017. PubMed ID: 29016666). It has been reported in an individual from a healthy, ancestry diverse cohort (Table S1, Bodian et al. PubMed ID: 24728327). The results of RT-PCR analysis suggest this variant does not impact splicing (eTable, Karam et al. 2019. PubMed ID: 31642931). It has also been reported as a somatically-acquired alteration in a pleomorphic xanthoastrocytoma (Table 1, Chan et al. 2017. PubMed ID: 28699883). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68835573-T-G). It has conflicting interpretation for likely benign and uncertain significance in ClinVar. Although we suspect that this variant may be benign, 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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Uncertain significance
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004240422.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 21, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684372.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with glycine at codon 55 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces valine with glycine at codon 55 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with breast cancer and colorectal cancer, but also in unaffected individuals (PMID: 24969172, 28135145, 28944238, 24728327, 33471991; [FLOSSIES database](https://whi.color.com/variant/16-68835573-T-G)). This variant has been identified in 7/282786 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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Likely benign
(Sep 01, 2022)
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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: SCV000321508.10
First in ClinVar: Jul 09, 2018 Last updated: Mar 04, 2023 |
Comment:
See Variant Classification Assertion Criteria.
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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: SCV004019606.1
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
(Oct 29, 2018)
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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: SCV000186188.8
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 19, 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: SCV000785172.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Likely benign
(Feb 10, 2022)
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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: SCV000919114.2
First in ClinVar: Jun 02, 2019 Last updated: Mar 12, 2022 |
Comment:
Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence, and impacts the … (more)
Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence, and impacts the first nucleotide of exon 3. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. Lack of impact on splicing was confirmed by RNA sequencing studies (Karam_2019). The variant allele was found at a frequency of 2.4e-05 in 251390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.164T>G, has been reported in the literature in individuals affected with colon cancer, breast cancer cases and controls and recurrent pregnancy loss (Yurgelun_2017, DeRycke_2017, Quintero-Ronderos_2017, Dorling_2021) . These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Eight clinical diagnostic laboratories including one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters have classified as VUS while 3 submitters including an expert panel have classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Jan 12, 2022)
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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: SCV002529082.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CDH1 c.164T>G (p.V55G) variant has been reported in heterozygosity in at least 5 individuals with hereditary diffuse gastric cancer syndrome, colorectal cancer, breast cancer … (more)
The CDH1 c.164T>G (p.V55G) variant has been reported in heterozygosity in at least 5 individuals with hereditary diffuse gastric cancer syndrome, colorectal cancer, breast cancer and recurrent pregnancy loss (PMID: 31511843, 28135145, 29016666, 24969172, 28944238), but has also been found in healthy controls (PMID: 24728327). It has been reported in 11/60466 cases and 14/53461 controls in a large case-control study of breast cancer (PMID: 33471991). It was observed in 7/129106 chromosomes in the Non-Finnish European (NFE) subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 132769). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (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: SCV003926998.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
BS2 (PMID: 30311375)
Geographic origin: Europe
Comment on evidence:
1 family not fulfilling 2020 HDGC criteria-Familial history of gastric+breast cancer
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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: SCV000153979.15
First in ClinVar: Jun 03, 2014 Last updated: Feb 14, 2024 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000084664.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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 |
Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. | Karam R | JAMA network open | 2019 | PMID: 31642931 |
Patients' Medical and Psychosocial Experiences After Detection of a CDH1 Variant With Multigene Panel Testing. | Hamilton JG | JCO precision oncology | 2019 | PMID: 31511843 |
Novel genes and mutations in patients affected by recurrent pregnancy loss. | Quintero-Ronderos P | PloS one | 2017 | PMID: 29016666 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history. | Chan AK | Clinical neuropathology | 2017 | PMID: 28699883 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer. | Wen H | BMC cancer | 2014 | PMID: 24969172 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/87528509-8592-44e0-bf92-b276bdd488fa | - | - | - | - |
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Text-mined citations for rs587778174 ...
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.