NM_004360.5(CDH1):c.1476_1477del (p.Arg492fs) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 29, 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:: RCV000554611.14

Allele description [Variation Report for NM_004360.5(CDH1):c.1476_1477del (p.Arg492fs)]

NM_004360.5(CDH1):c.1476_1477del (p.Arg492fs)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.1476_1477del (p.Arg492fs)

HGVS:

NC_000016.10:g.68815666AG[2]
NG_008021.1:g.83375AG[2]
NM_001317184.2:c.1293_1294del
NM_001317185.2:c.-77AG[2]
NM_001317186.2:c.-348AG[2]
NM_004360.5:c.1476_1477delMANE SELECT
NP_001304113.1:p.Arg431fs
NP_004351.1:p.Arg492fs
LRG_301t1:c.1476_1477del
LRG_301:g.83375AG[2]
NC_000016.10:g.68815670_68815671delAG
NC_000016.9:g.68849569AG[2]
NC_000016.9:g.68849569_68849570del
NM_004360.3(CDH1):c.1476_1477delAG
NM_004360.3:c.1476_1477del
NM_004360.3:c.1476_1477delAG
NM_004360.4:c.1476_1477del
p.Arg492Serfs

Protein change:

R431fs

Links:

dbSNP: rs876659208

NCBI 1000 Genomes Browser:

rs876659208

Molecular consequence:

NM_001317185.2:c.-77AG[2] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-348AG[2] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.1293_1294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004360.5:c.1476_1477del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000637726	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20373070, 15235021, 22020549, 28492532
SCV003926799	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018))	Pathogenic (Aug 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30311375, 26072394, 36436516
SCV004043611	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jun 13, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000637726

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

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

SCV003926799

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS

criteria provided, single submitter

(Lee et al. (Hum Mutat. 2018))

Pathogenic
(Aug 1, 2022)

germline

clinical testing

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

SCV004043611

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Jun 13, 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	yes	not provided	1	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

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

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 (7)

Details of each submission

From Invitae, SCV000637726.8

#	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.Arg492Serfs*44) 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 individuals with gastric cancer (PMID: 15235021, 22020549). ClinVar contains an entry for this variant (Variation ID: 231528). 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 European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS, SCV003926799.1

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

Description

"1 family fulfilling 2020 HDGC criteria-Familial history of gastric cancer"

PubMed [ID: 26072394]

Description

PVS1; PS4_Supporting; PM2 (PMID: 30311375)

#	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	1	not provided

From Myriad Genetics, Inc., SCV004043611.2

#	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

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine