16-68808831-C-T

Position:

chr16-68808831-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.670C>T (p.Arg224Cys) 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 (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288074/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

CDH1
NM_001317185.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign reviewed by expert panel B:21

Conservation

PhyloP100: -3.58

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 Likely_benign. Variant got -4 ACMG points.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.670C>T	p.Arg224Cys	missense_variant	5/16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.670C>T	p.Arg224Cys	missense_variant	5/16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

250896

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000391

AC:

572

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000473

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000217

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000339

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CDH1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26182300, 21106365, 25980754, no PMID, 25593300, 26893459, 27582386, 28301460, 27621404, 30311375, 29577179) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 22, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 20, 2024	The missense variant NM_004360.5(CDH1):c.670C>T (p.Arg224Cys) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 127932 as of 2024-08-01). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Likely Benign. -

Hereditary diffuse gastric adenocarcinoma

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely 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	BS2 (PMID: 30311375) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2025	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2019	Variant summary: CDH1 c.670C>T (p.Arg224Cys) results in a non-conservative amino acid change located in the Cadherin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251344 control chromosomes, predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 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 Non-Finnish European origin (ACMG BS1). c.670C>T has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, breast cancer, and colon cancer (Corso_2011, Harismendy_2013, Mouradov_2014, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (APC c.5582_5585delCTTT, p.Ser1861fsX1) as well as a co-occurence with a mutation in another gene (not explicitly specified) that clearly explains a proband's phenotype as mentioned in the supporting evidence shared by another submitting laboratory to the ClinVar database. These findings providing supporting evidence for a benign role (ACMG BP5). Cells expressing the p.Arg224Cys sequence variant maintained the ability to form compact aggregates at a similar level to that of the wild-type CDH1 expressing cells and retained capacity to prevent invasion in clear contrast to what was observed for mock cells; therefore, the c.670C>T (p.Arg224Cys) missense mutation does not impair E-cadherin induced cell adhesion and invasion in vitro (Corso_2011). However, an expert panel (ClinGen Hereditary Cancer) has reviewed the available literature and stated "none of the currently published in vitro and in vivo functional studies could be confidently used to predict pathogenicity of E-cadherin missense variants and therefore functional assays for missense alteration should not be used for CDH1 variant classificat" (Thompson_2018). Four clinical diagnostic laboratories and one expert panel (ClinGen Hereditary Cancer Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All labs classified the variant as likely benign while the expert panel classified the variant as VUS based on BS2 as the only criteria met by this variant. A follow-up with Dr. Xuo Li as the ClinGen CDH1 contact indicated that the committee was in agreement that a single BS code is sufficient to reach a likely benign classification, although it was not officially released at the time of this re-evaluation and a new version of the guideline was to be expected (personal correspondence, 05-14-19). Based on the evidence outlined above, we have utilized ACMG criteria BS2 (Expert Panel evidence) along with BS1 and BP5 (summarized above) and classified the variant as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 10, 2021

- -

CDH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 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). -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CDH1 p.Arg224Cys variant was identified in the literature however the frequency of this variant in an affected population was not provided (Corso 2011). The variant was also identified in dbSNP (ID: rs200310662) as â€šÃ„ÃºWith Likely benignâ€šÃ„Ã¹ and â€šÃ„ÃºUncertain significance alleleâ€šÃ„Ã¹, ClinVar (as likely benign by GeneDx, Invitae, Ambry Genetics, and Paul Sabatier University), Clinvitae (as likely benign), Cosmic (in large intestine and breast tissue), and LOVD 3.0 (1x as "effect unknown"). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database. The variant was identified in control databases in 47 of 276620 chromosomes at a frequency of 0.00017 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24024 chromosomes (freq: 0.000083), Latino in 1 of 34400 chromosomes (freq: 0.000029), European (Non-Finnish) in 35 of 126242 chromosomes (freq: 0.000277), European (Finnish) in 1 of 25758 chromosomes (freq: 0.000039), and South Asian in 8 of 30760 chromosomes (freq: 0.00026) while the variant was not observed in the Other, Ashkenazi Jewish, and East Asian populations. A functional analysis by Corso et al (2011) in which they compared the cell adhesion activity of the variant, they found the p.Arg224Cys expressing cells behaved in a similar manner to cells transduced with the wild-type CDH1. The study therefore concluded that the variant is non-pathogenic. In addition, the variant has been found in our lab to co-occur with a pathogenic BRCA1 variant c.135-1G>T, increasing the likelihood that the p.Arg224Cys variant does not have clinical significance. The p.Arg224Cys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Malignant tumor of prostate

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.670C>T (p.Arg224Cys) 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 (Variant Interpretation Guidelines Version 3.1): BS2. -

Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Uncertain

0.55

D;T;T;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.97

D;T;D;T;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.4

L;.;.;.;L

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.3

D;.;.;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.010

D;.;.;.;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.65

P;.;.;.;.

Vest4

0.18

MVP

0.72

MPC

0.56

ClinPred

0.059

GERP RS

-12

Varity_R

0.31

gMVP

0.19

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