NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 21, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000492731.7

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 cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580704	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 21, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23709761, 27880784, 29769627 Citation Link,
SCV002588962	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580704

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 21, 2020)

germline

clinical testing

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

Citation Link,

SCV002588962

BRCAlab, Lund University

no assertion criteria provided

Pathogenic
(Aug 26, 2022)

germline

clinical testing

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

Citations

PubMed

CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study.

Benusiglio PR, Malka D, Rouleau E, De Pauw A, Buecher B, Noguès C, Fourme E, Colas C, Coulet F, Warcoin M, Grandjouan S, Sezeur A, Laurent-Puig P, Molière D, Tlemsani C, Di Maria M, Byrde V, Delaloge S, Blayau M, Caron O.

J Med Genet. 2013 Jul;50(7):486-9. doi: 10.1136/jmedgenet-2012-101472. Epub 2013 May 25.

PubMed [citation]

PMID:: 23709761

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site.

Yelskaya Z, Bacares R, Salo-Mullen E, Somar J, Lehrich DA, Fasaye GA, Coit DG, Tang LH, Stadler ZK, Zhang L.

PLoS One. 2016;11(11):e0165654. doi: 10.1371/journal.pone.0165654.

PubMed [citation]

PMID:: 27880784
PMCID:: PMC5120775

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000580704.6

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

Description

The c.1679C>G variant (also known as p.T560R), located in coding exon 11 of the CDH1 gene, results from a C to G substitution at nucleotide position 1679. The threonine at codon 560 is replaced by arginine, an amino acid with similar properties. This nucleotide position is not well conserved in available vertebrate species. Multiple studies have described this alteration in families meeting diagnostic criteria for Hereditary Diffuse Gastric Cancer syndrome. In addition, this alteration has been observed to segregate with disease in at least 4 families (Benusiglio PR et al. J. Med. Genet. 2013 Jul;50:486-9; Yelskaya Z et al. PLoS ONE 2016 Nov;11(11):e0165654; Pena-Couso L et al. Eur. J. Hum. Genet. 2018 09;26(9):1348-1353). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA assay has demonstrated the creation of a novel splice donor site causing a frameshift and premature protein truncation (Yelskaya Z et al. PLoS ONE 2016 Nov;11(11):e0165654; Pena-Couso L et al. Eur. J. Hum. Genet. 2018 09;26(9):1348-1353). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 BRCAlab, Lund University, SCV002588962.1

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

#	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

Last Updated: Jul 15, 2024

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