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NM_004360.5(CDH1):c.2450C>T (p.Ala817Val) AND CDH1-related diffuse gastric and lobular breast cancer syndrome

Germline classification:
Likely benign (1 submission)
Last evaluated:
Sep 25, 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:
RCV003993820.1

Allele description [Variation Report for NM_004360.5(CDH1):c.2450C>T (p.Ala817Val)]

NM_004360.5(CDH1):c.2450C>T (p.Ala817Val)

Gene:
CDH1:cadherin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q22.1
Genomic location:
Preferred name:
NM_004360.5(CDH1):c.2450C>T (p.Ala817Val)
Other names:
NM_004360.5(CDH1):c.2450C>T
HGVS:
  • NC_000016.10:g.68833300C>T
  • NG_008021.1:g.101009C>T
  • NM_001317184.2:c.2267C>T
  • NM_001317185.2:c.902C>T
  • NM_001317186.2:c.485C>T
  • NM_004360.5:c.2450C>TMANE SELECT
  • NP_001304113.1:p.Ala756Val
  • NP_001304114.1:p.Ala301Val
  • NP_001304115.1:p.Ala162Val
  • NP_004351.1:p.Ala817Val
  • LRG_301t1:c.2450C>T
  • LRG_301:g.101009C>T
  • NC_000016.9:g.68867203C>T
  • NM_004360.3:c.2450C>T
  • NM_004360.4:c.2450C>T
  • p.A817V
Protein change:
A162V
Links:
dbSNP: rs587782024
NCBI 1000 Genomes Browser:
rs587782024
Molecular consequence:
  • NM_001317184.2:c.2267C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317185.2:c.902C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317186.2:c.485C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004360.5:c.2450C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004812906ClinGen CDH1 Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CDH1 ACMG Specifications V3.1)		Likely Benign
(Sep 25, 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, SCV004812906.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.2450C>T (p.Ala817Val) variant results in a missense change in the last exon of CDH1. This variant is present at a frequency 3.3x10-5 (5 of 152,172 alleles) in the gnomAD population database v3.1.2. This variant has been observed in 104 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In vitro studies of the A817V variant suggest reduced binding of B-catenin and reduced cell aggregation in a HEK293T cell model (PMID: 33929593). However, evaluation of the use of functional data by the VCEP indicates that functional data currently available for missense variants cannot yet predict the pathogenicity of CDH1 variants, and it is therefore not considered in the classification for any CDH1 missense variant (Lee et al, 2018; PMID: 30311375). As such, published information from in vitro or in vivo assays assessing impact on function for this missense variant has not been considered for variant curation. In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2.

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

Last Updated: Nov 3, 2024