rs142498771

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.394G>A (p.Val132Ile) 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/CA168677/MONDO:0100488/007

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:8

Conservation

PhyloP100: -3.01

Publications

9 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	UniProt
CDH1	NM_004360.5 link	c.394G>A	p.Val132Ile	missense_variant	Exon 4 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.394G>A	p.Val132Ile	missense_variant	Exon 4 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.-1222G>A		5_prime_UTR_variant	Exon 4 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-1426G>A		5_prime_UTR_variant	Exon 4 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.394G>A	p.Val132Ile	missense_variant	Exon 4 of 16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251326

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111988

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.000138

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41512

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000153

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:2Benign:1

Nov 11, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome

Benign:3

May 31, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 12, 2019

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. -

Sep 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer (Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 25186627) -

CDH1-related disorder

Uncertain:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CDH1 c.394G>A variant is predicted to result in the amino acid substitution p.Val132Ile. This variant has been identified in an individual with breast cancer (Supplementary data, Tung et al. 2015. PubMed ID: 25186627), as well as in an individual with colorectal cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142546/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Jun 16, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDH1 c.394G>A (p.Val132Ile) 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 5.3e-05 in 282708 control chromosomes, predominantly at a frequency of 0.00048 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.394G>A has been reported in the literature in sequencing studies of individuals affected with breast cancer and colorectal cancer (example, Tung_2015, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=3; VUS, n=3) with an emerging consensus towards a benign outcome since its previous evaluation. Based on the evidence outlined above, the variant was re-classified as benign. -

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.394G>A (p.Val132Ile) 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

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.024

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.29

T;T;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.72

T;T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.054

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;.;L

PhyloP100

-3.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.10

N;.;.;.;N

REVEL

Benign

0.051

Sift

Benign

0.23

T;.;.;.;T

Sift4G

Benign

0.42

T;T;T;T;T

Polyphen

0.32

B;.;.;.;.

Vest4

0.056

MVP

0.36

MPC

0.21

ClinPred

0.041

GERP RS

-11

Varity_R

0.040

gMVP

0.061

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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