16-68828262-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.2253C>T (p.Asn751=) variant has an allele frequency of 0.10006 (10%, 3546/35438 alleles, 185 homozygotes) in the Latino subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA167533/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.039 ( 142 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1031 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: -2.44

Publications

48 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: Benign. The variant received -9 ACMG points.

BP2

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.2253C>T	p.Asn751Asn	synonymous_variant	Exon 14 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.2070C>T	p.Asn690Asn	synonymous_variant	Exon 13 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.705C>T	p.Asn235Asn	synonymous_variant	Exon 14 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.288C>T	p.Asn96Asn	synonymous_variant	Exon 13 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.2253C>T	p.Asn751Asn	synonymous_variant	Exon 14 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0391

AC:

5949

AN:

152028

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0514

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0691

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0731

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.0153

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0280

Gnomad OTH

AF:

0.0326

GnomAD2 exomes

AF:

0.0429

AC:

10791

AN:

251474

AF XY:

0.0400

show subpopulations

Gnomad AFR exome

AF:

0.0544

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0765

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0373

GnomAD4 exome

AF:

0.0330

AC:

48303

AN:

1461686

Hom.:

1031

Cov.:

AF XY:

0.0327

AC XY:

23784

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0547

AC:

1830

AN:

33480

American (AMR)

AF:

0.0950

AC:

4250

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

348

AN:

26136

East Asian (EAS)

AF:

0.0744

AC:

2954

AN:

39692

South Asian (SAS)

AF:

0.0396

AC:

3415

AN:

86242

European-Finnish (FIN)

AF:

0.0174

AC:

930

AN:

53414

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5768

European-Non Finnish (NFE)

AF:

0.0292

AC:

32458

AN:

1111852

Other (OTH)

AF:

0.0330

AC:

1993

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2583

5166

7749

10332

12915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1374

2748

4122

5496

6870

<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

AF:

0.0392

AC:

5965

AN:

152146

Hom.:

142

Cov.:

AF XY:

0.0398

AC XY:

2959

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0514

AC:

2133

AN:

41520

American (AMR)

AF:

0.0691

AC:

1055

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.0723

AC:

374

AN:

5172

South Asian (SAS)

AF:

0.0410

AC:

198

AN:

4824

European-Finnish (FIN)

AF:

0.0153

AC:

162

AN:

10584

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0280

AC:

1901

AN:

67990

Other (OTH)

AF:

0.0393

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

276

552

829

1105

1381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0356

Hom.:

Bravo

AF:

0.0449

Asia WGS

AF:

0.0810

AC:

279

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0279

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary diffuse gastric adenocarcinoma

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 23, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:2

Apr 02, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Prostate cancer

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CDH1 p.Asn751Asn variant was identified in 57 of 2080 proband chromosomes (frequency: 0.0274038461538462) from individuals or families with gastric cancer (Becker 1994, Berx 1997, Chen 2013, Chu 2014, Fang 2013, Zhang 2006). The variant was also identified in dbSNP (rs: rs33964119) with benign allele, ClinVar (4x as benign), Cosmic (as neutral), and the Zhejiang Colon Cancer Database (4x). The variant was not identified in MutDB, or Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 11569 of 277194 chromosomes at a frequency of 0.041736 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: Latino in 3462 (181 homozygous) of 34416 chromosomes (freq: 0.101), East Asian in 1459 (64 homozygous) of 18858 chromosomes (freq: 0.077), African in 1243 (39 homozygous) of 24026 chromosomes (freq: 0.052), South Asian in 1355 (48 homozygous) of 30782 chromosomes (freq: 0.044), Other in 232 (5 homozygous) of 6468 chromosomes (freq: 0.036), European (Non-Finnish) in 3253 (38 homozygous) of 126698 chromosomes (freq: 0.026), European (Finnish) in 448 of 25794 chromosomes (freq: 0.017). In addition, several studies classify the variant as a benign polymorphism (Berx 1997, Chen 2013, Chu 2014, Milne 2007). The p.Asn751Asn variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Aug 10, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_004360.5(CDH1):c.2253C>T (p.Asn751=) variant has an allele frequency of 0.10006 (10%, 3546/35438 alleles, 185 homozygotes) in the Latino subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.56

(source)

DANN

Benign

0.82

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over