VCV001778959.6 - ClinVar

NM_004360.5(CDH1):c.172G>T (p.Glu58Ter)

Germline

Classification

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.

(5)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.172G>T (p.Glu58Ter)

Variation ID: 1778959 Accession: VCV001778959.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68801678 (GRCh38) [ NCBI UCSC ] 16: 68835581 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 29, 2022	May 1, 2024	Dec 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.172G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Glu58Ter	nonsense
NM_001317184.2:c.172G>T	NP_001304113.1:p.Glu58Ter	nonsense
NM_001317185.2:c.-1444G>T		5 prime UTR
NM_001317186.2:c.-1648G>T		5 prime UTR
NC_000016.10:g.68801678G>T
NC_000016.9:g.68835581G>T
NG_008021.1:g.69387G>T
LRG_301:g.69387G>T
LRG_301t1:c.172G>T	LRG_301p1:p.Glu58Ter

... more HGVS ... less HGVS

Protein change

E58*

Other names

Canonical SPDI

NC_000016.10:68801677:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
CDH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4456	4550

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.
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 8, 2022	RCV002407409.3
Hereditary diffuse gastric adenocarcinoma	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 17, 2023	RCV003336713.4
Familial cancer of breast	Likely pathogenic (1)	criteria provided, single submitter	Jun 15, 2023	RCV003464533.1

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.
Pathogenic (Jun 08, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004043354.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Likely pathogenic (Jun 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215714.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Dec 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004366595.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 15235021‚ 20373070 Comment: This sequence change creates a premature translational stop signal (p.Glu58) in the CDH1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu58) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1778959). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004360436.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27064202‚ 30935944 Comment: This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual with no history of diffuse gastric cancer but was found affected with signet ring cell carcinoma (SRCC) upon endoscopy (PMID: 30935944), and in several members of one family reporting no history of diffuse gastric cancer (PMID: 27064202). Clinical laboratories have classified numerous other truncations in exon 3 of CDH1 as pathogenic in ClinVar. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (May 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002716717.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27064202 Comment: The p.E58* pathogenic mutation (also known as c.172G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at … (more) The p.E58* pathogenic mutation (also known as c.172G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 172. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Glu58*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1778959). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual with no history of diffuse gastric cancer but was found affected with signet ring cell carcinoma (SRCC) upon endoscopy (PMID: 30935944), and in several members of one family reporting no history of diffuse gastric cancer (PMID: 27064202). Clinical laboratories have classified numerous other truncations in exon 3 of CDH1 as pathogenic in ClinVar. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.E58* pathogenic mutation (also known as c.172G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 172. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Outcomes of Endoscopic Surveillance in Individuals With Genetic Predisposition to Hereditary Diffuse Gastric Cancer.	Jacobs MF	Gastroenterology	2019	PMID: 30935944
Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.	Huynh JM	Molecular genetics & genomic medicine	2016	PMID: 27064202
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

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.172G>T (p.Glu58Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...