rs199886166

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.1297G>A (p.Asp433Asn) 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/CA288028/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000079 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:7B:11

Conservation

PhyloP100: 3.89

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.1297G>A	p.Asp433Asn	missense_variant	9/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2 linkuse as main transcript	c.-319G>A		5_prime_UTR_variant	9/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-523G>A		5_prime_UTR_variant	9/15		NP_001304115.1
CDH1	NM_001317184.2 linkuse as main transcript	c.1137+1209G>A		intron_variant			NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1297G>A	p.Asp433Asn	missense_variant	9/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251484

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jun 21, 2018	This sequence variant is a single nucleotide substitution (G>A) that results in an aspartic acid to asparagine amino acid change at residue 433 in the CDH1 protein. The variant is rare, and is present in 3/120502 alleles (0.002%) in the ExAC database. The variant has been observed in a sporadic gastric cancer patient (PMID: 23435907) and at least two women with breast cancer, including one case of lobular breast cancer (PMID: 20921021) and one breast cancer of unspecified type (PMID: 26976419). This variant lies in cadherin repeat domain 3, but the aspartic acid at this position is not well conserved in this domain; several mammalian species have asparagine at this position. Additionally, the variant lies near a splice site, but mRNA analysis indicates no effects on proper splicing (PMID: 23435907). The majority of in silico tools queried predict that substituting asparagine for aspartic acid at this protein position will have a neutral effect on protein function. However, no functional tests to confirm these predictions have been performed, to our knowledge. At this time, we consider this to be a variant of uncertain significance. -
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 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 17, 2016	- -

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2020	The CDH1 c.1297G>A; p.Asp433Asn variant (rs199886166) has been described in the literature in individuals with breast cancer without causality of the variant established (Momozawa 2018, Schrader 2011). The variant has been classified as likely benign by an expert panel in the ClinVar database but is also classified as a variant of uncertain significance by several sources (Variation ID: 127910). The variant is found in the general population with an overall allele frequency of 0.005% (13/251,484 alleles) in the Genome Aggregation Database. The aspartic acid at codon 433 is moderately conserved computational analyses predict that this variant is neutral (REVEL: 0.09). Due to limited information, the clinical significance of the p.Asp433Asn variant is uncertain at this time. References: Momozawa et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Schrader et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011 Jan;48(1):64-8. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CDH1: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Asp433Asn variant was identified in 4 of 2232 proband chromosomes (frequency: 0.002) from individuals or families with lobular breast carcinoma, metanephric adenoma or gastric cancer and was not identified in 850 control chromosomes from healthy individuals (Ding 2018, Li 2013, Schrader 2011, Tung 2016). The variant was also identified in dbSNP (ID: rs199886166) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and four other submitters). The variant was identified in control databases in 12 of 246262 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111710 chromosomes (freq: 0.00002), Ashkenazi Jewish in 8 of 9850 chromosomes (freq: 0.0008), and East Asian in 2 of 17248 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Finnish, and South Asian populations. RNA analysis of the p.Asp433Asn variant demonstrated normal-length mRNA, suggesting this variant does not induce splicing defects in E-cadherin (Li 2013). The p.Asp433 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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) 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or gastric cancer (Schrader 2011, Li 2013, Tung 2016, Momozawa 2018); This variant is associated with the following publications: (PMID: 22722839, 30287823, 20921021, 23435907, 26976419, 26759166, 25096233, 26486520, 26182300) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2015	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: CDH1 c.1297G>A (p.Asp433Asn) results in a conservative amino acid change located in the Cadherrin-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 5.2e-05 in 252334 control chromosomes. The observed variant frequency is approximately 2 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 benign. The variant has been reported in the literature in breast and gastric cancer patients, without strong evidence for causality (Schrader_2010, Tung_2016, Li_2013). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. One functional study reported the variant to have no impact on splicing, yielding normal-sized mRNA (Li_2013), however additional functional studies have not been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22722839, 20921021, 26976419, 23435907, 30287823, 28061482). 15 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

CDH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 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

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.1297G>A (p.Asp433Asn) 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.93

L;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;.;.;.

REVEL

Benign

0.090

Sift

Benign

0.089

T;.;.;.

Sift4G

Benign

0.061

T;T;T;T

Polyphen

0.14

B;.;.;.

Vest4

0.24

MVP

0.76

MPC

0.27

ClinPred

0.11

GERP RS

2.8

Varity_R

0.093

gMVP

0.46

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