16-68819393-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP3PM2_SupportingPS3PS4PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID:27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID:27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID:27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS3, PP1_Strong, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10577547/MONDO:0007648/007

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10U:1

Conservation

PhyloP100: 1.21

Publications

20 publications found

Variant links:

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

CDH1 Gene-Disease associations (from GenCC):

blepharocheilodontic syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
CDH1-related diffuse gastric and lobular breast cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary diffuse gastric adenocarcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
cleft soft palate
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
orofacial cleft 3
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
blepharocheilodontic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CDH1 links:

ENSG00000260798 (HGNC:):

ENSG00000260798 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH1	NM_004360.5 link	c.1679C>G	p.Thr560Arg	missense_variant	Exon 11 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.1496C>G	p.Thr499Arg	missense_variant	Exon 10 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.131C>G	p.Thr44Arg	missense_variant	Exon 11 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-254-2608C>G		intron_variant	Intron 10 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.1679C>G	p.Thr560Arg	missense_variant	Exon 11 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:4

Jun 14, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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]. -

Familial Cancer Clinical Unit, Spanish National Cancer Research Centre (CNIO)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing;in vitro

- -

Jul 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 altered 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. -

Aug 01, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3; PS4; PM2; PP1_Strong; PP3 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

May 31, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aug 26, 2022

BRCAlab, Lund University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jun 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDH1 c.1679C>G (p.Thr560Arg) variant activates a cryptic splice donor site and has been shown in the published literature to cause aberrant mRNA splicing and the production of a truncated CDH1 transcript (PMID: 27880784 (2016)). Further experimental studies showed this variant has deleterious effects on CDH1 protein function (PMID: 29769627 (2018)). This variant has been reported in multiple individuals with diffused gastric cancer and lobular breast cancer (PMIDs: 36436516 (2022), 34949788 (2022), 29769627 (2018), 23709761 (2013)), and segregated with disease in at least two families with HDGC (PMIDs: 33268956 (2020), 27880784 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Pathogenic:1

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS3, PP1_Strong, PS4. -

Familial cancer of breast

Pathogenic:1

Sep 20, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Oct 14, 2015

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in at least one individual diagnosed with early-onset diffuse gastric cancer (Benusiglio 2013). CDH1 Thr560Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. CDH1 Thr560Arg occurs at a position that is conserved in mammals and is located in the Cadherin 4 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDH1 Thr560Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T;T;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.84

T;T;T;T;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.5

L;.;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

D;.;.;.;D

REVEL

Benign

0.20

Sift

Benign

0.039

D;.;.;.;D

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.75

MutPred

0.50

Gain of methylation at T560 (P = 0.0363);Gain of methylation at T560 (P = 0.0363);.;Gain of methylation at T560 (P = 0.0363);.;

MVP

0.84

MPC

0.97

ClinPred

0.98

GERP RS

4.6

Varity_R

0.41

gMVP

0.65

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over