rs200911775

Positions:

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.2635G>A (p.Gly879Ser) 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/CA288064/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:15

Conservation

PhyloP100: 6.88

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
CDH1	NM_004360.5 linkuse as main transcript	c.2635G>A	p.Gly879Ser	missense_variant	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.2452G>A	p.Gly818Ser	missense_variant	15/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.1087G>A	p.Gly363Ser	missense_variant	16/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.670G>A	p.Gly224Ser	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.2635G>A	p.Gly879Ser	missense_variant	16/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251410

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.000246

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000157

AC:

230

AN:

1461520

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000193

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 26123647, 25067988, 25980754, 25925381, 30287823) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CDH1: BP1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2022	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	Variant summary: CDH1 c.2635G>A (p.Gly879Ser) results in a non-conservative amino acid change located in the cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277608 control chromosomes, predominantly at a frequency of 0.00025 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 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. c.2635G>A has been reported in the literature in individuals with suspected Lynch syndrome or affected with lobular breast cancer (Valente_2014, Yurgelun_ 2015) without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. 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: 25980754, 25067988, 26123647, 28166811, 30311375, 30287823). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=12) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 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	Color Diagnostics, LLC DBA Color Health	Mar 04, 2020	- -

Hereditary diffuse gastric adenocarcinoma

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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) -

CDH1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

The CDH1 c.2635G>A variant is predicted to result in the amino acid substitution p.Gly879Ser. This variant has been reported in individuals with a history of breast cancer and suspected Lynch syndrome (Table 2, Valente et al. 2014. PubMed ID: 25067988; Supplemental Table 2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68867388-G-A). This variant has been classified as likely benign by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127928). 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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CDH1 p.Gly879Ser variant was identified in 4 of 16,822 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or lynch syndrome and was present in 1 of 47,462 control chromosomes (frequency: 0.00002) from healthy individuals (Momozawa 2018, Yurgelun 2015, Valente 2014). The variant was identified in dbSNP (rs200911775) as â€š with other alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by ClinGen CDH1 Curation Panel, Invitae, Color and 1 other submitter; and as likely benign by Ambry Genetics, GeneDx and Integrated Genetics). The variant was identified in control databases in 37 of 282,800 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 7218 chromosomes (freq: 0.0003), European in 32 of 129,134 chromosomes (freq: 0.0002), African in 1 of 24,964 chromosomes (freq: 0.00004), Finnish in 1 of 25,106 chromosomes (freq: 0.00004), and Latino in 1 of 35,440 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Gly879 residue is 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) 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. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 19, 2018

- -

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.2635G>A (p.Gly879Ser) 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. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

D;T;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

D;.;D

REVEL

Uncertain

0.37

Sift

Benign

0.054

T;.;T

Sift4G

Benign

0.084

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.40

MVP

0.89

MPC

0.90

ClinPred

0.51

GERP RS

6.2

Varity_R

0.29

gMVP

0.28

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