rs587781898

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.184G>A (p.Gly62Ser) variant has been observed in >10 individuals 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, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA166005/MONDO:0100488/007

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:8B:6

Conservation

PhyloP100: 3.05

Publications

9 publications found

Variant links:

COSMIC-nc: COSV104558685

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: Likely_benign. The variant received -4 ACMG points.

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.184G>A	p.Gly62Ser	missense_variant	Exon 3 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.184G>A	p.Gly62Ser	missense_variant	Exon 3 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.-1432G>A		5_prime_UTR_variant	Exon 3 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-1636G>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.184G>A	p.Gly62Ser	missense_variant	Exon 3 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251428

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1111836

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41404

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

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:

0.0000564

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4

May 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colorectal cancer, and also in unaffected controls (Shirts et al., 2016; Dominguez-Valentin et al., 2018; Erdem et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 29371908, 10357799, 26845104, 32283892, 33471991, 35089076) -

Jan 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDH1 c.184G>A (p.Gly62Ser) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 32283892 (2020)) and breast cancer (PMIDs: 34326862 (2021), 26845104 (2016)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). The frequency of this variant in the general population, 0.000046 (6/129132 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Aug 23, 2017

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 19, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Feb 10, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 21, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the CDH1 gene demonstrated a sequence change, c.184G>A, in exon 3 that results in an amino acid change, p.Gly62Ser. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP NA). The p.Gly62Ser change has been described in individuals with breast cancer (PMID: 29371908). The p.Gly62Ser change affects a highly conserved amino acid residue located in a domain of the CDH1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly62Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly62Ser change remains unknown at this time. -

Jan 15, 2024

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.184G>A (p.Gly62Ser) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.184G>A has been reported in the literature in individuals affected with breast cancer, colorectal cancer, and unreported cancer type (Shirts_2016, Dominguez-Valentin_2018, Erdem_2020, Sahin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26845104, 29371908, 32283892, 35089076). ClinVar contains an entry for this variant (Variation ID: 141639). The variant was classified as uncertain significance by 9 sumitters and likely benign by 3 submitters including a ClinGen expert panel. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary diffuse gastric adenocarcinoma

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ovarian cancer

Uncertain:1

Jun 02, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Aug 03, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_004360.5(CDH1):c.184G>A (p.Gly62Ser) variant has been observed in >10 individuals 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, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.2

M;.;.;.;M

PhyloP100

3.1

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.9

D;.;.;.;D

REVEL

Benign

0.28

Sift

Benign

0.075

T;.;.;.;T

Sift4G

Benign

0.23

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.20

MutPred

0.83

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.88

MPC

0.61

ClinPred

0.84

GERP RS

5.4

Varity_R

0.19

gMVP

0.46

Mutation Taster

=67/33

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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rs587781898

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