chr16-68828254-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8130235/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:10

Conservation

PhyloP100: 1.28

Publications

25 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

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.2245C>T	p.Arg749Trp	missense_variant	Exon 14 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.2062C>T	p.Arg688Trp	missense_variant	Exon 13 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.697C>T	p.Arg233Trp	missense_variant	Exon 14 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 13 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.2245C>T	p.Arg749Trp	missense_variant	Exon 14 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152080

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251478

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Alfa

AF:

0.0000165

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:1Uncertain:2

Feb 16, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 749 of the CDH1 protein (p.Arg749Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 17545690). ClinVar contains an entry for this variant (Variation ID: 418841). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17545690, 18772194, 19268661, 22850631, 25388006, 34486077). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 14, 2020

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:3

May 25, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted CDH1 c.2245C>T at the cDNA level, p.Arg749Trp (R749W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been suggested in several in vitro based assays to result in reduced E-cadherin surface expression and cell-cell adhesion, as well as increased cell motility and invasion compared to wild type controls (Kaurah 2007, Simoes-Correia 2008, Mateus 2009, Figueiredo 2013). While CDH1 Arg749Trp has also been observed in a family with three cases of gastric cancer, two of which are reported as diffuse gastric cancer, segregation analysis was not completed (Kaurah 2007). CDH1 Arg749Trp was not observed in large population cohorts. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Arg749Trp is located in the cytoplasmic domain and Hakai p120-catenin binding regions (Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. While there are in vitro functional assays suggesting pathogenicity, internal observations at this laboratory and other clinical laboratories are not suggestive of hereditary diffuse gastric cancer. Based on currently available evidence, it is unclear whether CDH1 Arg749Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

May 08, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Apr 28, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R749W variant (also known as c.2245C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide position 2245. The arginine at codon 749 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, located in the intracellular juxtamembrane domain of the CDH1 gene, has been reported in 1 of 38 families diagnosed clinically with hereditary diffuse gastric cancer (HDGC) who were analyzed for CDH1 mutations, however segregation analysis was not completed in this family (Kaurah P et al. JAMA, 2007 Jun;297:2360-72). Several in vitro based studies showed that this variant increased cell motility and invasion compared to wild type controls as well as reduced expression and interaction with E-cadherin (Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9; Sanches JM et al. Eur. J. Hum. Genet., 2015 Aug;23:1072-9; Mateus AR et al. Exp. Cell Res., 2009 May;315:1393-402; Mestre T et al. Sci Rep, 2016 05;6:25101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dec 14, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 749 of the CDH1 protein. Functional studies have shown the mutant protein to be defective in cell surface expression, cell adhesion, motility and cell invasion ability (PMID 17545690, 18772194, 19268661, 22850631). The severity of the defect differs broadly. This variant has been reported in a family with five individuals affected with gastric cancer (ages 36-49), two of whom with diffuse cancer, but each individual's genotype was not provided (PMID: 17545690). This variant has been observed in an individual affected with breast cancer (PMID: 30653559). This variant has been identified in 1/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Uncertain:1

Aug 28, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CDH1 p.Arg749Trp variant was identified in 1 of 76 proband chromosomes (frequency: 0.013) from individuals or families with Diffuse Gastric Cancer, the family included 2 cases of diffuse gastric cancer and one case of breast cancer however segregation analysis was not reported (Kaurah 2007). The variant was also identified in dbSNP (ID: rs776975632) as With Uncertain significance allele, in ClinVar and Clinvitae (classified as uncertain significance by GeneDx), Insight Colon Cancer Gene Variant Database, and the Zhejiang Colon Cancer database. GeneDx reports that the variant was observed in patients with phenotypes that are not suggestive of Hereditary Diffuse Gastric Cancer (ClinVar). The variant was not identified in the Cosmic or MutDB, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Several in vitro functional studies were identified on this variant that suggests that the variant is pathogenic. Multiple studies have displayed that the variant reduces the level of E-cadherin found at the cell membrane and retained the protein in the endoplasmic reticulum (Simoes-Correia 2008, Mateus 2009, Figueiredo 2013, Sanches 2015). One study displayed that the variant produces low total and surface E-cadherin expression, despite the normal RNA levels, because the variant reduces binding of E-cadherin to B-catenin increasing the likelihood of degradation due to ubiquitination (Figueiredo 2013). Kaurah et al. (2007) expressed the c.2245C>T variant in CHO cells and displayed that the variant failed to cause cell aggregation that the wildtype E-cadherin causes and the variant increased the invasion of E-cadherin into collagen matrices at significantly higher rates than wildtype. Additional groups have also displayed increased cell motility due to the c.2245C>T variant (Mateus 2009, Mestre 2016). The p.Arg749 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Dec 06, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.0

H;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.5

D;.;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.86

Loss of disorder (P = 0.0048);.;.;

MVP

0.97

MPC

0.92

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.86

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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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