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NM_004360.5(CDH1):c.103G>T (p.Glu35Ter) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Dec 10, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001193904.8

Allele description [Variation Report for NM_004360.5(CDH1):c.103G>T (p.Glu35Ter)]

NM_004360.5(CDH1):c.103G>T (p.Glu35Ter)

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.103G>T (p.Glu35Ter)
HGVS:
  • NC_000016.10:g.68738351G>T
  • NG_008021.1:g.6060G>T
  • NM_001317184.2:c.103G>T
  • NM_001317185.2:c.-1513G>T
  • NM_001317186.2:c.-1717G>T
  • NM_004360.5:c.103G>TMANE SELECT
  • NP_001304113.1:p.Glu35Ter
  • NP_004351.1:p.Glu35Ter
  • LRG_301t1:c.103G>T
  • LRG_301:g.6060G>T
  • NC_000016.9:g.68772254G>T
  • NM_004360.3:c.103G>T
  • NM_004360.4:c.103G>T
Protein change:
E35*
Links:
dbSNP: rs1597838625
NCBI 1000 Genomes Browser:
rs1597838625
Molecular consequence:
  • NM_001317185.2:c.-1513G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001317186.2:c.-1717G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001317184.2:c.103G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_004360.5:c.103G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary diffuse gastric adenocarcinoma (HDGC)
Synonyms:
Hereditary diffuse gastric cancer
Identifiers:
MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001363072Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Dec 10, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001389987Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 4, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer.

Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, Jordan EJ, Gao SP, Ramirez R, Cha EK, Desai NB, Zabor EC, Ostrovnaya I, Gopalan A, Chen YB, Fine SW, Tickoo SK, Gandhi A, Hreiki J, Viale A, Arcila ME, Dalbagni G, et al.

Nat Genet. 2016 Apr;48(4):356-8. doi: 10.1038/ng.3503. Epub 2016 Feb 22.

PubMed [citation]
PMID:
26901067
PMCID:
PMC4827439

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.

Sakr RA, Schizas M, Carniello JV, Ng CK, Piscuoglio S, Giri D, Andrade VP, De Brot M, Lim RS, Towers R, Weigelt B, Reis-Filho JS, King TA.

Mol Oncol. 2016 Feb;10(2):360-70. doi: 10.1016/j.molonc.2015.11.001. Epub 2015 Nov 14.

PubMed [citation]
PMID:
26643573
PMCID:
PMC4989916
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363072.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: CDH1 c.103G>T (p.Glu35X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 156712 control chromosomes (gnomAD). c.103G>T has been reported in the literature as a somatic variant in individuals affected with invasive lobular carcinoma (Sakr_2016), and plasmacytoid variant bladder cancer (Al-Ahmadie_2016). These reports do not provide unequivocal conclusions about the germline association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001389987.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has not been reported in the literature in individuals with CDH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu35*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product.

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

Last Updated: Sep 29, 2024