16-68833484-C-T

Position:

chr16-68833484-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.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 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/CA168961/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.016 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 139 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:19

Conservation

PhyloP100: -4.03

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP2

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

BA1

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.2634C>T	p.Gly878Gly	synonymous_variant	16/16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.2451C>T	p.Gly817Gly	synonymous_variant	15/15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.1086C>T	p.Gly362Gly	synonymous_variant	16/16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.669C>T	p.Gly223Gly	synonymous_variant	15/15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 link	c.2634C>T	p.Gly878Gly	synonymous_variant	16/16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2422

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00595

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.00690

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.00919

AC:

2311

AN:

251410

Hom.:

AF XY:

0.00850

AC XY:

1155

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0372

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.00743

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.00751

AC:

10977

AN:

1461474

Hom.:

139

Cov.:

AF XY:

0.00741

AC XY:

5385

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.0384

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.00968

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.00498

Gnomad4 NFE exome

AF:

0.00635

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0159

AC:

2424

AN:

152154

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1159

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0356

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00595

Gnomad4 NFE

AF:

0.00690

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.0181

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0107

EpiControl

AF:

0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 11, 2016	- -

Hereditary diffuse gastric adenocarcinoma

Benign:4

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 24, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
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) -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

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. -
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	Dec 01, 2017	- -

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.Gly878= variant was identified in 7 of 438 proband chromosomes (frequency: 0.02) from individuals or families with hereditary diffuse gastric cancer (Jakubowska 2010, Oliveira 2002, Guindalini 2019, El-Husny 2014). The variant was also identified in dbSNP (ID: rs2229044) as "With other allele" and ClinVar (classified as benign by Invitae, Ambry Genetics and two other submitters; and as likely benign by three submitters). The variant was identified in control databases in 2637 of 277164 chromosomes (47 homozygous) at a frequency of 0.009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 851 of 24030 chromosomes (freq: 0.04), Other in 122 of 6468 chromosomes (freq: 0.02), Latino in 430 of 34420 chromosomes (freq: 0.01), European in 911 of 126668 chromosomes (freq: 0.007), Ashkenazi Jewish in 112 of 10152 chromosomes (freq: 0.01), East Asian in 1 of 18864 chromosomes (freq: 0.00005), Finnish in 137 of 25780 chromosomes (freq: 0.005), and South Asian in 73 of 30782 chromosomes (freq: 0.002). The p.Gly878= 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) 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.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 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

-0.51

CADD

Benign

5.6

DANN

Benign

0.76

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