VCV002503034.5 - ClinVar

NM_004360.5(CDH1):c.385C>T (p.Gln129Ter)

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.

(4)

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

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.385C>T (p.Gln129Ter)

Variation ID: 2503034 Accession: VCV002503034.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68801891 (GRCh38) [ NCBI UCSC ] 16: 68835794 (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	Jun 4, 2023	Nov 10, 2024	Nov 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.385C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Gln129Ter	nonsense
NM_001317184.2:c.385C>T	NP_001304113.1:p.Gln129Ter	nonsense
NM_001317185.2:c.-1231C>T		5 prime UTR
NM_001317186.2:c.-1435C>T		5 prime UTR
NC_000016.10:g.68801891C>T
NC_000016.9:g.68835794C>T
NG_008021.1:g.69600C>T
LRG_301:g.69600C>T
LRG_301t1:c.385C>T	LRG_301p1:p.Gln129Ter

... more HGVS ... less HGVS

Protein change

Q129*

Other names

Canonical SPDI

NC_000016.10:68801890:C: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 diffuse gastric adenocarcinoma	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 3, 2024	RCV003229768.5
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Aug 17, 2023	RCV003459810.1

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 (Aug 01, 2022)	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	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: SCV003927031.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (1) PubMed: 36436516 Comment: PVS1; PS4_Moderate; PM2 (PMID: 30311375) Geographic origin: Europe Comment on evidence: 2 families fulfilling 2020 HDGC criteria-1 Familial history of gastric cancer; 1 Familial history of gastric+breast cancer
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: SCV004043505.2 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.
Pathogenic (Aug 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215664.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV005387778.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: This sequence change creates a premature translational stop signal (p.Gln129Ter) 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.Gln129Ter) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD (no frequency). This variant has been reported in individual(s) affected with Hereditary diffuse gastric adenocarcinoma (PMID: 30311375). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 3 submissions and no conflicts.. Therefore, this variant has been classified as pathogenic.Heterozygous variants in the CDH1 gene cause increased susceptibility to breast cancer (OMIM# 114480). (less) Age: 40-49 years Sex: female

Comment:

This sequence change creates a premature translational stop signal (p.Gln129Ter) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD (no frequency). This variant has been reported in individual(s) affected with Hereditary diffuse gastric adenocarcinoma (PMID: 30311375). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 3 submissions and no conflicts.. Therefore, this variant has been classified as pathogenic.Heterozygous variants in the CDH1 gene cause increased susceptibility to breast cancer (OMIM# 114480).

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
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

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.385C>T (p.Gln129Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...