rs570930882

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 c.1273G>A (p.Val425Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 6 in 152,140 alleles in the gnomAD v3.1.2 population database. This variant was observed in a proband with oral clefting (PMID:27227907). However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288025/MONDO:0100488/007

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:8

Conservation

PhyloP100: 1.49

Publications

14 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.1273G>A	p.Val425Ile	missense_variant	Exon 9 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2 link	c.-343G>A		5_prime_UTR_variant	Exon 9 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-547G>A		5_prime_UTR_variant	Exon 9 of 15		NP_001304115.1
CDH1	NM_001317184.2 link	c.1137+1185G>A		intron_variant	Intron 8 of 14		NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.1273G>A	p.Val425Ile	missense_variant	Exon 9 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

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:

0.0000398

AC:

AN:

251484

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1112002

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.0000394

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

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:

0.0000838

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

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.Val425Ile variant was not identified in the literature nor was it identified in the MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs570930882) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae), Cosmic (classified as neutral (score 0.31)), databases. The variant was identified in control databases in 9 of 277228 chromosomes at a frequency of 0.000032 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val425 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Cadherin-like functional domain, the clinical significance of which cannot be determined. 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. -

Apr 30, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

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

- -

Feb 28, 2023

GeneDx

Significance:Uncertain significance

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 endometrial or colorectal cancer and in an individual with oral clefting (Jori et al., 2015; Ittiwut et al., 2016; Do et al., 2022); This variant is associated with the following publications: (PMID: 24686850, 27227907, 26517685, 30287823, 32175104, 35098669, 31638429, 15235021, 22850631) -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1Benign:3

Feb 28, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2_Supporting (PMID: 30311375) -

Hereditary cancer-predisposing syndrome

Benign:2

Sep 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2020

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. -

not specified

Benign:1

Aug 14, 2023

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.1273G>A (p.Val425Ile) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of 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 5.1e-05 in 273966 control chromosomes (gnomAD and Momozawa_2018). The observed variant frequency is approximately 2.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1273G>A has been reported in the literature (e.g. Jori_2015, Kraemer_2019), but these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, a large Japanese case-control study found the variant to be not associated with breast cancer risk (Momozawa_2018). 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: 33309985, 26517685, 31422574, 30287823, 36243179). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments ranging from uncertain significance to benign, with the most common (four) being likely benign. Based on the evidence outlined above, the variant was classified as likely 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 c.1273G>A (p.Val425Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 6 in 152,140 alleles in the gnomAD v3.1.2 population database. This variant was observed in a proband with oral clefting (PMID:27227907). However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.8

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.19

T;T;T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.035

N;.;.;.

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.10

N;.;.;.

REVEL

Benign

0.078

Sift

Benign

1.0

T;.;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.021

B;.;.;.

Vest4

0.11

MutPred

0.57

Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);

MVP

0.66

MPC

0.26

ClinPred

0.044

GERP RS

4.1

Varity_R

0.041

gMVP

0.24

Mutation Taster

=98/2

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