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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 23, 2024
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:: RCV001193904.10

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:: DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME
Identifiers:: MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001363072	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 10, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26901067, 26643573 Citation Link,
SCV001389987	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 10, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15235021, 20373070, 28492532
SCV005403965	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jul 23, 2024)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001363072

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 10, 2021)

germline

clinical testing

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

Citation Link,

SCV001389987

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 10, 2024)

germline

clinical testing

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

SCV005403965

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Jul 23, 2024)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001389987.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 929049). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV005403965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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