rs587781329

Variant names:

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 c.160A>G (p.Arg54Gly) missense variant has a frequency of 0.00002737 (5 of 182,668) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004080 (3 of 73,538) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000183777.5, SCV000545364.6, SCV000210888.14). 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 (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA293951/MONDO:0007648/007

Frequency

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

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:7

Conservation

PhyloP100: -0.333

Publications

3 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: 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
CDH1	NM_004360.5 link	c.160A>G	p.Arg54Gly	missense_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.160A>G	p.Arg54Gly	missense_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.-1456A>G		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-1660A>G		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDH1	ENST00000261769.10 link	c.160A>G	p.Arg54Gly	missense_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6 link	c.160A>G	p.Arg54Gly	missense_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5 link	n.160A>G		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5 link	n.160A>G		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000264

AC:

AN:

151304

AF XY:

0.0000374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000416

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000344

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1392146

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

686140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31442

American (AMR)

AF:

0.0000282

AC:

AN:

35446

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

35530

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

1073716

Other (OTH)

AF:

0.000104

AC:

AN:

57630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000528

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 23, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDH1 c.160A>G (p.Arg54Gly) variant has been reported in the published literature in individuals with personal and/or family history of breast cancer (PMIDs: 25186627 (2015), 28202063 (2017)) and other CDH1-associated cancer (PMID: 36436516 (2023)). The frequency of this variant in the general population, 0.000041 (3/73538 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 16, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast or ovarian cancer (Tung et al., 2015; Jalkh et al., 2017); This variant is associated with the following publications: (PMID: 24908143, 28202063, 28873162, 25186627, 15235021) -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1Benign:1

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:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2_Supporting (PMID: 30311375) -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:2

Aug 17, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.160A>G (p.Arg54Gly) missense variant has a frequency of 0.00002737 (5 of 182,668) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004080 (3 of 73,538) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000183777.5, SCV000545364.6, SCV000210888.14). 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 (Variant Interpretation Guidelines Version 3.1): BS2. -

May 21, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Dec 21, 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. -

Aug 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDH1-related disorder

Benign:1

Jun 06, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.56

T;T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.58

D;D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

M;.;.;.;M

PhyloP100

-0.33

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.8

D;.;.;.;D

REVEL

Benign

0.22

Sift

Benign

0.044

D;.;.;.;T

Sift4G

Uncertain

0.013

D;D;D;D;D

Polyphen

0.85

P;.;.;.;.

Vest4

0.72

MutPred

0.68

Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);

MVP

0.81

MPC

0.52

ClinPred

0.85

GERP RS

3.6

Varity_R

0.51

gMVP

0.75

Mutation Taster

=75/25

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over