rs35572355

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1

This summary comes from the ClinGen Evidence Repository: The c.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (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). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157969/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:3U:4B:11O:1

Conservation

PhyloP100: 8.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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.2494G>A	p.Val832Met	missense_variant	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.2311G>A	p.Val771Met	missense_variant	15/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.946G>A	p.Val316Met	missense_variant	16/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.529G>A	p.Val177Met	missense_variant	15/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.2494G>A	p.Val832Met	missense_variant	16/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251488

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00431

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:3Uncertain:4Benign:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:1Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	BS1; BS2 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2019	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	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2017	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2020	Variant summary: CDH1 c.2494G>A (p.Val832Met) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 253888 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 60 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 East Asian origin. c.2494G>A, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Yabuta_2002, Kim_2017), Breast Cancer (Schrader_2011, Rummel_2017, Siraj_2017), Lynch Syndrome (Yurgelun_2015), and Pancreatic Cancer (Shindo_2017, Ohmoto_2015). A publication, Yabuta_2002, reports the variant to segregate with disease in a HDGC family. Furthermore, a tumor obtained from a patient with this variant harbored a CDH1 promoter hypermethylation as a second hit leading to somatic loss of heterozygosity (Oliveira_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed (Siraj_2017-FANCI c.2737C>T, p.Q913X; our laboratory-BRCA2 c.5576_5579delTTAA, p.Ile1859fs), providing supporting evidence for a benign role. Multiple functional studies showed no significant effect of this variant on cell mobility and cell invasion (Suriano_2003), interaction with alpha/beta catenin (Bajpai_2008), cell surface expression, EGFR signaling, and beta catenin binding (Mateaus_2009, Yabuta_2002, Curtis_2007). In addition, Clinical Genome Resource (ClinGen) variant curation expert panel (VCEP) recently classified this variant as benign (Lee_2018). Ten clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (likely benign, n=3, benign, n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2019	This variant is associated with the following publications: (PMID: 12216071, 26759166, 28004449, 26692440, 20373070, 29050249, 16924464, 19268661, 22850631, 24055113, 24728327, 17668349, 12944922, 17261850, 16600987, 25388006, 25856671, 25637381, 17545690, 20233471, 26150395, 20921021, 16787116, 28503720, 14500541, 19269290, 26049741, 25980754, 22470475, 19017792, 29231860, 28975465, 28767289, 29522266, 29929997, 29752822, 16112667, 21989054, 19247957, 31159747, 31892987, 32426482) -

Neoplasm of stomach

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 10, 2002

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

CDH1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 21, 2020

This variant is classified as 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 10, 2023

The c.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (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). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;T;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.5

N;.;N

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.69

MVP

0.94

MPC

0.91

ClinPred

0.35

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.80

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

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