NM_004360.5(CDH1):c.602_603del (p.Pro201fs) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 10, 2025
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:: RCV003064355.7

Allele description [Variation Report for NM_004360.5(CDH1):c.602_603del (p.Pro201fs)]

NM_004360.5(CDH1):c.602_603del (p.Pro201fs)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.602_603del (p.Pro201fs)

HGVS:

NC_000016.10:g.68808763_68808764del
NG_008021.1:g.76472_76473del
NM_001317184.2:c.602_603del
NM_001317185.2:c.-1014_-1013del
NM_001317186.2:c.-1218_-1217del
NM_004360.5:c.602_603delMANE SELECT
NP_001304113.1:p.Pro201fs
NP_004351.1:p.Pro201Argfs
NP_004351.1:p.Pro201fs
LRG_301t1:c.602_603del
LRG_301:g.76472_76473del
LRG_301p1:p.Pro201Argfs
NC_000016.9:g.68842666_68842667del
NM_004360.3:c.602_603delCT

Protein change:

P201fs

Molecular consequence:

NM_001317185.2:c.-1014_-1013del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1218_-1217del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.602_603del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004360.5:c.602_603del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV003443629	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15235021, 20373070, 24389957, 28492532
SCV004042966	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jun 9, 2023)	unknown	clinical testing	Citation Link,
SCV005685087	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 10, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24389957, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443629

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 17, 2023)

germline

clinical testing

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

SCV004042966

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Jun 9, 2023)

unknown

clinical testing

Citation Link,

SCV005685087

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 10, 2025)

germline

clinical testing

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

Help

Summary from all submissions

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

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

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice.

Guilford P, Humar B, Blair V.

Gastric Cancer. 2010 Mar;13(1):1-10. doi: 10.1007/s10120-009-0531-x. Epub 2010 Apr 7. Review.

PubMed [citation]

PMID:: 20373070

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443629.3

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

Description

This sequence change creates a premature translational stop signal (p.Pro201Argfs*7) 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 premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 24389957). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137843). 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., SCV004042966.2

#	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 frameshift 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

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV005685087.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The following ACMG criteria was used: PVS1; PM2_SUP; PP1

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

Last Updated: Feb 25, 2025

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