NM_004360.5:c.1896C>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.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African 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/CA165821/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.020 ( 57 hom., cov: 31)

Exomes 𝑓: 0.0081 ( 165 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:20

Conservation

PhyloP100: -4.77

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:

ENSG00000260798 (HGNC:):

ENSG00000260798 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.1896C>T	p.His632His	synonymous_variant	Exon 12 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.1896C>T	p.His632His	synonymous_variant	Exon 12 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3008

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0486

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0106

AC:

2670

AN:

251464

AF XY:

0.00978

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.00806

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.00810

AC:

11839

AN:

1461840

Hom.:

165

Cov.:

AF XY:

0.00801

AC XY:

5826

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0536

AC:

1795

AN:

33476

American (AMR)

AF:

0.0156

AC:

697

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00876

AC:

229

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86256

European-Finnish (FIN)

AF:

0.00520

AC:

278

AN:

53416

Middle Eastern (MID)

AF:

0.0870

AC:

502

AN:

5768

European-Non Finnish (NFE)

AF:

0.00657

AC:

7308

AN:

1111968

Other (OTH)

AF:

0.0137

AC:

827

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

626

1251

1877

2502

3128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.0198

AC:

3022

AN:

152256

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1451

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0489

AC:

2032

AN:

41530

American (AMR)

AF:

0.0171

AC:

261

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68012

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

148

296

444

592

740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0125

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary diffuse gastric adenocarcinoma

Benign:5

Sep 20, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1; BP2_Strong (PMID: 30311375) -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

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. -

Nov 15, 2017

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 02, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.His632= variant was identified in 7 of 716 proband chromosomes (frequency: 0.010) from Polish, Italian and multiethnic cohorts of individuals or families with hereditary diffuse gastric cancer, nonhereditary or at risk gastric cancer and breast cancer (invasive lobular carcinoma), and was present in 7 of 304 control chromosomes (frequency: 0.02) from healthy individuals (Jakubowska 2010, Oliveira 2002, Valente 2014 , Garziera 2013). In one study, individuals found to carry the variant were those at risk of gastric cancer but not with sporadic gastric cancer (Garziera 2013). The variant has been reported as a polymorphism (frequency unspecified), in several studies (Berx 1997, Gayther 1998). The variant was identified in dbSNP (ID: rs33969373) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar database (classification benign by Ambry Genetics, Prevention Genetics, Illumina, Color Genomics and Invitae), Clinvitae (3X classified as benign), Cosmic (2X in a haemangioblastoma and thyroid tumor), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB, or Insight Colon Cancer Gene Variant Database. The variant was also identified in control databases in 3105 (57 homozygous) of 277164 chromosomes at a frequency of 0.0112, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27 2017); being identified in the following populations at a frequency greater than 1%: African in 1191 of 24012 chromosome (freq: 0.05), Other in 128 of 6464 chromosomes (freq. 0.02), Latino in 477 of 34418 chromosomes (freq. 0.014), and in Ashkenazi Jewish in 103 of 10152 chromosomes (freq. 0.010). The p.His632His 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.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African 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

-0.74

CADD

Benign

0.26

(source)

DANN

Benign

0.82

PhyloP100

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

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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