rs553907248

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2BP2_StrongBS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This 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). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA090925/MONDO:0100488/007

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense, splice_region

Scores

Clinical Significance

Benign reviewed by expert panel U:6B:7

Conservation

PhyloP100: 8.11

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP2

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

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/exons	MANE	Protein
CDH1	NM_004360.5 linkuse as main transcript	c.1568A>G	p.Tyr523Cys	missense_variant, splice_region_variant	11/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.1385A>G	p.Tyr462Cys	missense_variant, splice_region_variant	10/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.20A>G	p.Tyr7Cys	missense_variant, splice_region_variant	11/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-254-2719A>G		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1568A>G	p.Tyr523Cys	missense_variant, splice_region_variant	11/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1
	ENST00000563916.1 linkuse as main transcript	n.264-3623T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251482

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000164

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.000351

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 06, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 21, 2023	The CDH1 c.1568A>G (p.Tyr523Cys) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is located adjacent to the acceptor splice site of intron 10, however it is not predicted to affect splicing. Canonical splice site variants affecting this acceptor site are predicted to result in an in-frame insertion with a potential rescue transcript (PMID: 36600593). This variant has been identified in BRCA1/2-negative breast cancer patients, however it is unknown if these individuals had lobular breast cancer (PMID: 29522266, 31780696). To our knowledge, this variant has not been reported in the literature in individuals with diffuse gastric and lobular breast cancer syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces tyrosine with cysteine at codon 523 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 29522266, 31780696). This variant has been identified in 9/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2020	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 10, 2021	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	Variant summary: CDH1 c.1568A>G (p.Tyr523Cys) results in a non-conservative amino acid change located in the Cadherin-like domian (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 151000 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.0015 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 53 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 Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	Observed in individuals with breast cancer (Hauke 2018, Dutil 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27181684, 29522266, 31780696, 32936981) -

CDH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 03, 2023

The filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This 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). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;T;T;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.2

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.4

D;.;.;.;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.72

Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);.;Loss of MoRF binding (P = 0.084);.;

MVP

0.93

MPC

1.0

ClinPred

1.0

GERP RS

5.5

Varity_R

0.80

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over