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NM_004360.5(CDH1):c.2526del (p.Ala843fs) AND CDH1-related diffuse gastric and lobular breast cancer syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 21, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003328479.4

Allele description [Variation Report for NM_004360.5(CDH1):c.2526del (p.Ala843fs)]

NM_004360.5(CDH1):c.2526del (p.Ala843fs)

Gene:
CDH1:cadherin 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
16q22.1
Genomic location:
Preferred name:
NM_004360.5(CDH1):c.2526del (p.Ala843fs)
HGVS:
  • NC_000016.10:g.68833376del
  • NG_008021.1:g.101085del
  • NM_001317184.2:c.2343del
  • NM_001317185.2:c.978del
  • NM_001317186.2:c.561del
  • NM_004360.5:c.2526delMANE SELECT
  • NP_001304113.1:p.Ala782fs
  • NP_001304114.1:p.Ala327fs
  • NP_001304115.1:p.Ala188fs
  • NP_004351.1:p.Ala843fs
  • LRG_301:g.101085del
  • NC_000016.9:g.68867279del
Protein change:
A188fs
Links:
dbSNP: rs1961538047
NCBI 1000 Genomes Browser:
rs1961538047
Molecular consequence:
  • NM_001317184.2:c.2343del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001317185.2:c.978del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001317186.2:c.561del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_004360.5:c.2526del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
CDH1-related diffuse gastric and lobular breast cancer syndrome
Synonyms:
CDH1-related diffuse gastric and lobular breast cancer
Identifiers:
MONDO: MONDO:0100488; MedGen: CN311521

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001437606ClinGen CDH1 Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CDH1 ACMG Specifications V3.1)		Uncertain significance
(Aug 21, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen CDH1 Variant Curation Expert Panel, SCV001437606.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.2526del (p.Ala843LeufsTer3) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). One family meets the HDGC criteria (PS4_Supporting; Internal lab contributor). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS4_Supporting. This VUS variant is trending to the pathogenic side. The CDH1 VCEP will re-evaluate it, if more evidence emerge in the future.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024