VCV002137843.8 - ClinVar

NM_004360.5(CDH1):c.602_603del (p.Pro201fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.602_603del (p.Pro201fs)

Variation ID: 2137843 Accession: VCV002137843.8

Type and length

Deletion, 2 bp

Location

Cytogenetic: 16q22.1 16: 68808763-68808764 (GRCh38) [ NCBI UCSC ] 16: 68842666-68842667 (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	Feb 8, 2023	Feb 25, 2025	Jan 10, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.602_603del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Pro201fs	frameshift
NM_001317184.2:c.602_603del	NP_001304113.1:p.Pro201fs	frameshift
NM_001317185.2:c.-1014_-1013del		5 prime UTR
NM_001317186.2:c.-1218_-1217del		5 prime UTR
NC_000016.10:g.68808763_68808764del
NC_000016.9:g.68842666_68842667del
NG_008021.1:g.76472_76473del
LRG_301:g.76472_76473del
LRG_301t1:c.602_603del	LRG_301p1:p.Pro201Argfs

... more HGVS ... less HGVS

Protein change

P201fs

Other names

Canonical SPDI

NC_000016.10:68808762:CT:

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

ClinGen: CA2580091933 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	4837	4932

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 diffuse gastric adenocarcinoma	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 10, 2025	RCV003064355.7
not provided	Likely pathogenic (1)	criteria provided, single submitter	Mar 15, 2022	RCV003138469.3

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 09, 2023) C Contributing to aggregate classification	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: SCV004042966.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Likely pathogenic (Mar 15, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823048.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005685087.1 First in ClinVar: Feb 01, 2025 Last updated: Feb 01, 2025	Publications: PubMed (1) PubMed: 24389957 Comment: The following ACMG criteria was used: PVS1; PM2_SUP; PP1
Pathogenic (Dec 17, 2023) C Contributing to aggregate classification	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: SCV003443629.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 15235021‚ 20373070‚ 24389957 Comment: This sequence change creates a premature translational stop signal (p.Pro201Argfs7) 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.Pro201Argfs7) 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 premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 24389957). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137843). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Pro201Argfs*7) 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 premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 24389957). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137843). For these reasons, this variant has been classified as Pathogenic.

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
Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations-a clinical observational study.	Bardram L	Familial cancer	2014	PMID: 24389957
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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.602_603del (p.Pro201fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...