NM_004360.5(CDH1):c.309G>A (p.Trp103Ter) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 8, 2023
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:: RCV001949646.7

Allele description [Variation Report for NM_004360.5(CDH1):c.309G>A (p.Trp103Ter)]

NM_004360.5(CDH1):c.309G>A (p.Trp103Ter)

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.309G>A (p.Trp103Ter)

HGVS:

NC_000016.10:g.68801815G>A
NG_008021.1:g.69524G>A
NM_001317184.2:c.309G>A
NM_001317185.2:c.-1307G>A
NM_001317186.2:c.-1511G>A
NM_004360.5:c.309G>AMANE SELECT
NP_001304113.1:p.Trp103Ter
NP_004351.1:p.Trp103Ter
LRG_301:g.69524G>A
NC_000016.9:g.68835718G>A

Protein change:

W103*

Links:

dbSNP: rs2152126900

NCBI 1000 Genomes Browser:

rs2152126900

Molecular consequence:

NM_001317185.2:c.-1307G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1511G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.309G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004360.5:c.309G>A - 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
SCV002247349	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31514334, 15235021, 20373070, 28492532
SCV004043690	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jun 8, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002247349

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 14, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004043690

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Jun 8, 2023)

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

Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition.

Tedaldi G, Pirini F, Tebaldi M, Zampiga V, Cangini I, Danesi R, Arcangeli V, Ravegnani M, Abou Khouzam R, Molinari C, Oliveira C, Morgagni P, Saragoni L, Bencivenga M, Ulivi P, Amadori D, Martinelli G, Falcini F, Ranzani GN, Calistri D.

Cancers (Basel). 2019 Sep 11;11(9). doi: 10.3390/cancers11091340.

PubMed [citation]

PMID:: 31514334
PMCID:: PMC6769562

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, et al.

J Med Genet. 2004 Jul;41(7):508-17.

PubMed [citation]

PMID:: 15235021
PMCID:: PMC1735838

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002247349.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (PMID: 31514334). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp103*) 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).

#	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., SCV004043690.2

#	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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