NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 5, 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:: RCV000678243.18

Allele description [Variation Report for NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg)]

NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg)

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.1679C>G (p.Thr560Arg)

Other names:

NM_004360.4(CDH1):c.1679C>G

HGVS:

NC_000016.10:g.68819393C>G
NG_008021.1:g.87102C>G
NM_001317184.2:c.1496C>G
NM_001317185.2:c.131C>G
NM_001317186.2:c.-254-2608C>G
NM_004360.5:c.1679C>GMANE SELECT
NP_001304113.1:p.Thr499Arg
NP_001304114.1:p.Thr44Arg
NP_004351.1:p.Thr560Arg
LRG_301t1:c.1679C>G
LRG_301:g.87102C>G
NC_000016.9:g.68853296C>G
NM_004360.3:c.1679C>G
NM_004360.4:c.1679C>G

Protein change:

T44R

Links:

dbSNP: rs746481984

NCBI 1000 Genomes Browser:

rs746481984

Molecular consequence:

NM_001317186.2:c.-254-2608C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1496C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1679C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000693437	Familial Cancer Clinical Unit, Spanish National Cancer Research Centre (CNIO)	no assertion criteria provided	Pathogenic	germline, not applicable	clinical testing, in vitro
SCV000815215	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23709761, 30745422, 27880784, 29769627, 28492532
SCV003926827	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, 27880784, 36436516
SCV004044208	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jun 14, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23709761, 26182300, 27880784 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	4	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
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
Caucasian	germline	yes	7	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC).

Lo W, Zhu B, Sabesan A, Wu HH, Powers A, Sorber RA, Ravichandran S, Chen I, McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MM, Hewitt SM, Koh C, Heller T, Wacholder S, Rudloff U.

J Med Genet. 2019 Jun;56(6):370-379. doi: 10.1136/jmedgenet-2018-105361. Epub 2019 Feb 11.

PubMed [citation]

PMID:: 30745422
PMCID:: PMC6716162

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer.

Pena-Couso L, Perea J, Melo S, Mercadillo F, Figueiredo J, Sanches JM, Sánchez-Ruiz A, Robles L, Seruca R, Urioste M.

Eur J Hum Genet. 2018 Sep;26(9):1348-1353. doi: 10.1038/s41431-018-0173-8. Epub 2018 May 16.

PubMed [citation]

PMID:: 29769627
PMCID:: PMC6117277

See all PubMed Citations (8)

Details of each submission

From Familial Cancer Clinical Unit, Spanish National Cancer Research Centre (CNIO), SCV000693437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	not provided
2	Caucasian	7	not provided	not provided	clinical testing	not provided

Description

CDH1 p.T560R cells showed: reduced CDH1 protein expression levels, altered localization of the protein in the cell, reduced cell-cell adhesion and increased invasiveness of mutant cells.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		7	not provided	3	not provided

From Invitae, SCV000815215.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 560 of the CDH1 protein (p.Thr560Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with diffuse gastric cancer (PMID: 23709761, 27880784, 29769627, 30745422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234554). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in activation of a cryptic donor splice site and introduces a premature termination codon (PMID: 27880784, 29769627). The resulting mRNA is expected to undergo nonsense-mediated decay. 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, SCV003926827.1

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

Description

"4 families fulfilling 2020 HDGC criteria-2 Familial history of gastric+breast cancer; 2 Familial history of gastric cancer"

PubMed [ID: 27880784]

Description

PS3; PS4; PM2; PP1_Strong; PP3 (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	4	not provided

From Myriad Genetics, Inc., SCV004044208.2

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

Description

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 27880784]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23709761, 26182300, 27880784].

#	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: Jun 23, 2024

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