NM_004360.5:c.188G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS2BS1

This summary comes from the ClinGen Evidence Repository: The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the “Other” subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, 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): BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288048/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:11

Conservation

PhyloP100: 0.326

Publications

6 publications found

Variant links:

COSMIC-nc: COSV99028634

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 -8 ACMG points.

BS1

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

BS2

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.188G>A	p.Arg63Gln	missense_variant	Exon 3 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.188G>A	p.Arg63Gln	missense_variant	Exon 3 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.-1428G>A		5_prime_UTR_variant	Exon 3 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-1632G>A		5_prime_UTR_variant	Exon 3 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.188G>A	p.Arg63Gln	missense_variant	Exon 3 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

251434

AF XY:

0.0000883

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:

0.0000352

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111960

Other (OTH)

AF:

0.0000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

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:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2084

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

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:1Benign:3

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.Arg63Gln variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or in the Zhejiang University database. The variant was identified in dbSNP (ID: rs587780117) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Geneitcs, Invitae). The variant was identified in control databases in 17 of 246200 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.00007), Other in 6 of 5486 chromosomes (freq: 0.001), European in 3 of 111650 chromosomes (freq: 0.00003), and South Asian in 7 of 30782 chromosomes (freq: 0.0002); it was not observed in the Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg63 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Feb 22, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: BS1, BP4 -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

Hereditary cancer-predisposing syndrome

Benign:3

May 18, 2018

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. -

Sep 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Uncertain:1Benign:1

Dec 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 23, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDH1 c.188G>A (p.Arg63Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251434 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05). To our knowledge, no occurrence of c.188G>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 127919). Based on the evidence outlined above, the variant was classified as likely benign. -

CDH1-related disorder

Benign:1

Feb 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the Other subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, 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): BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.9

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;.;.;.;L

PhyloP100

0.33

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.3

N;.;.;.;N

REVEL

Benign

0.053

Sift

Benign

0.34

T;.;.;.;T

Sift4G

Benign

0.59

T;T;T;T;T

Polyphen

0.097

B;.;.;.;.

Vest4

0.15

MVP

0.77

MPC

0.31

ClinPred

0.024

GERP RS

2.2

Varity_R

0.031

gMVP

0.23

Mutation Taster

=92/8

polymorphism

(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