16-68822185-C-T

Position:

chr16-68822185-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA165821/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.020 ( 57 hom., cov: 31)

Exomes 𝑓: 0.0081 ( 165 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: -4.77

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 -9 ACMG points.

BP2

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.1896C>T	p.His632=	synonymous_variant	12/16	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.1713C>T	p.His571=	synonymous_variant	11/15
CDH1	NM_001317185.2 linkuse as main transcript	c.348C>T	p.His116=	synonymous_variant	12/16
CDH1	NM_001317186.2 linkuse as main transcript	c.-70C>T		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1896C>T	p.His632=	synonymous_variant	12/16	1	NM_004360.5	P1	P12830-1
	ENST00000563916.1 linkuse as main transcript	n.263+1079G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3008

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0486

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.0248

GnomAD3 exomes

AF:

0.0106

AC:

2670

AN:

251464

Hom.:

AF XY:

0.00978

AC XY:

1329

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.00806

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.00810

AC:

11839

AN:

1461840

Hom.:

165

Cov.:

AF XY:

0.00801

AC XY:

5826

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0536

Gnomad4 AMR exome

AF:

0.0156

Gnomad4 ASJ exome

AF:

0.00876

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.00520

Gnomad4 NFE exome

AF:

0.00657

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.0198

AC:

3022

AN:

152256

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1451

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0489

Gnomad4 AMR

AF:

0.0171

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.00725

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary diffuse gastric adenocarcinoma

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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	BA1; BP2_Strong (PMID: 30311375) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CDH1 p.His632= variant was identified in 7 of 716 proband chromosomes (frequency: 0.010) from Polish, Italian and multiethnic cohorts of individuals or families with hereditary diffuse gastric cancer, nonhereditary or at risk gastric cancer and breast cancer (invasive lobular carcinoma), and was present in 7 of 304 control chromosomes (frequency: 0.02) from healthy individuals (Jakubowska 2010, Oliveira 2002, Valente 2014 , Garziera 2013). In one study, individuals found to carry the variant were those at risk of gastric cancer but not with sporadic gastric cancer (Garziera 2013). The variant has been reported as a polymorphism (frequency unspecified), in several studies (Berx 1997, Gayther 1998). The variant was identified in dbSNP (ID: rs33969373) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar database (classification benign by Ambry Genetics, Prevention Genetics, Illumina, Color Genomics and Invitae), Clinvitae (3X classified as benign), Cosmic (2X in a haemangioblastoma and thyroid tumor), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB, or Insight Colon Cancer Gene Variant Database. The variant was also identified in control databases in 3105 (57 homozygous) of 277164 chromosomes at a frequency of 0.0112, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27 2017); being identified in the following populations at a frequency greater than 1%: African in 1191 of 24012 chromosome (freq: 0.05), Other in 128 of 6464 chromosomes (freq. 0.02), Latino in 477 of 34418 chromosomes (freq. 0.014), and in Ashkenazi Jewish in 103 of 10152 chromosomes (freq. 0.010). The p.His632His variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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, this variant meets our laboratory's criteria to be classified as benign. -

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 NM_004360.5(CDH1):c.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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): BA1, BP2. -

Malignant tumor of prostate

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.26

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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