VCV000449339.17 - ClinVar

NM_004360.5(CDH1):c.1590dup (p.Asn531fs)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for CDH1-related diffuse gastric and lobular breast cancer syndrome

Classification is based on the expert panel submission

Aug 2023 by ClinGen CDH1 Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.1590dup (p.Asn531fs)

Variation ID: 449339 Accession: VCV000449339.17

Type and length

Duplication, 1 bp

Location

Cytogenetic: 16q22.1 16: 68819302-68819303 (GRCh38) [ NCBI UCSC ] 16: 68853205-68853206 (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	Sep 26, 2017	Feb 25, 2025	Aug 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5(CDH1):c.1590dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004360.5:c.1590dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Asn531fs	frameshift
NM_001317184.2:c.1407dup	NP_001304113.1:p.Asn470fs	frameshift
NM_001317185.2:c.42dup	NP_001304114.1:p.Asn15fs	frameshift
NM_001317186.2:c.-254-2697dup		intron variant
NM_004360.3:c.1590dupC
NC_000016.10:g.68819304dup
NC_000016.9:g.68853207dup
NG_008021.1:g.87013dup
LRG_301:g.87013dup
LRG_301t1:c.1590dup

... more HGVS ... less HGVS

Protein change

N15fs, N470fs, N531fs

Other names

Canonical SPDI

NC_000016.10:68819302:CC:CCC

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: CA658658491 OMIM: 192090.0014 dbSNP: rs1555516535 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.
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 1, 2017	RCV000520434.2
CDH1-related diffuse gastric and lobular breast cancer syndrome	Pathogenic (1)	reviewed by expert panel	Aug 25, 2023	RCV003328390.2
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Jan 19, 2023	RCV003464107.1
Hereditary diffuse gastric adenocarcinoma	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 14, 2023	RCV001260576.12

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 (Aug 25, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen CDH1 ACMG Specifications V3.1) Method: curation	CDH1-related diffuse gastric and lobular breast cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen CDH1 Variant Curation Expert Panel FDA Recognized Database Accession: SCV001437619.2 First in ClinVar: Oct 10, 2020 Last updated: Sep 20, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/552d88d5-40c6-4f5f-a451-3c5da270c6db Comment: The c.1590dup (p.Asn531fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant … (more) The c.1590dup (p.Asn531fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). This variant has been reported in a family meeting HDGC clinical criteria (PS4_Supporting, PMID: 10477433). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. (less)
Pathogenic (Mar 01, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617357.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: This duplication of one nucleotide in CDH1 is denoted c.1590dupC at the cDNA level and p.Asn531GlnfsX6 (N531QfsX6) at the protein level. The normal sequence, with … (more) This duplication of one nucleotide in CDH1 is denoted c.1590dupC at the cDNA level and p.Asn531GlnfsX6 (N531QfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTGC[dupC]AACT. The duplication causes a frameshift which changes an Asparagine to a Glutamine at codon 531, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDH1 c.1590dupC, also known as 1588insC using alternate nomenclature, has been reported in a Hereditary Diffuse Gastric Cancer family (Guilford 1999). We consider this variant to be pathogenic. (less)
Pathogenic (Jun 14, 2023) N Not 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: SCV004043531.2 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.
Pathogenic (Jan 19, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215753.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Apr 07, 2023) N Not 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: SCV002235966.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 10477433‚ 15235021‚ 20373070 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449339). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449339). This premature translational stop signal has been observed in individual(s) with gastric cancer (PMID: 10477433). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn531Glnfs*6) 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). (less)
Pathogenic (Jul 01, 2001) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033275.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2024	Publications: PubMed (2) PubMed: 10477433‚ 11443625 Comment on evidence: In a family segregating diffuse gastric cancer (DGLBC; 137215), Guilford et al. (1999) identified a 1-bp insertion (1588insC) in exon 11 of the CDH1 gene. … (more) In a family segregating diffuse gastric cancer (DGLBC; 137215), Guilford et al. (1999) identified a 1-bp insertion (1588insC) in exon 11 of the CDH1 gene. Chun et al. (2001) reported total gastrectomy as a prophylactic intervention in all 5 affected members of a family with diffuse gastric cancer and the 1588insC mutation. (less)

Comment:

The c.1590dup (p.Asn531fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). This variant has been reported in a family meeting HDGC clinical criteria (PS4_Supporting, PMID: 10477433). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting.

Comment:

This duplication of one nucleotide in CDH1 is denoted c.1590dupC at the cDNA level and p.Asn531GlnfsX6 (N531QfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTGC[dupC]AACT. The duplication causes a frameshift which changes an Asparagine to a Glutamine at codon 531, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDH1 c.1590dupC, also known as 1588insC using alternate nomenclature, has been reported in a Hereditary Diffuse Gastric Cancer family (Guilford 1999). We consider this variant to be pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449339). This premature translational stop signal has been observed in individual(s) with gastric cancer (PMID: 10477433). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn531Glnfs*6) 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).

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
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
Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated?	Chun YS	Cancer	2001	PMID: 11443625
E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer.	Guilford PJ	Human mutation	1999	PMID: 10477433
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/552d88d5-40c6-4f5f-a451-3c5da270c6db	-	-	-	-

Text-mined citations for rs1555516535 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.1590dup (p.Asn531fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555516535 ...