rs33963999

Positions:

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.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 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/CA169542/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.038 ( 175 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2440 hom. )

Consequence

CDH1
NM_004360.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 0.855

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:

CDH1 (HGNC:):

CDH1 links:

Genome browser will be placed here

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	Effect	MANE	Protein	UniProt
CDH1	NM_004360.5 linkuse as main transcript	c.531+10G>C	intron_variant	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 linkuse as main transcript	c.531+10G>C	intron_variant		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 linkuse as main transcript	c.-1085+10G>C	intron_variant		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 linkuse as main transcript	c.-1289+10G>C	intron_variant		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.531+10G>C		intron_variant		1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

5790

AN:

152172

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0320

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0536

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0580

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0385

AC:

9672

AN:

251068

Hom.:

254

AF XY:

0.0391

AC XY:

5312

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00910

Gnomad AMR exome

AF:

0.0218

Gnomad ASJ exome

AF:

0.0399

Gnomad EAS exome

AF:

0.000436

Gnomad SAS exome

AF:

0.0214

Gnomad FIN exome

AF:

0.0586

Gnomad NFE exome

AF:

0.0546

Gnomad OTH exome

AF:

0.0389

GnomAD4 exome

AF:

0.0538

AC:

78655

AN:

1461656

Hom.:

2440

Cov.:

AF XY:

0.0527

AC XY:

38312

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00833

Gnomad4 AMR exome

AF:

0.0237

Gnomad4 ASJ exome

AF:

0.0396

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0216

Gnomad4 FIN exome

AF:

0.0600

Gnomad4 NFE exome

AF:

0.0612

Gnomad4 OTH exome

AF:

0.0493

GnomAD4 genome

AF:

0.0380

AC:

5792

AN:

152290

Hom.:

175

Cov.:

AF XY:

0.0381

AC XY:

2840

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0319

Gnomad4 ASJ

AF:

0.0435

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0536

Gnomad4 NFE

AF:

0.0581

Gnomad4 OTH

AF:

0.0425

Alfa

AF:

0.0492

Hom.:

Bravo

AF:

0.0343

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

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

not provided

Benign:3

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 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary diffuse gastric adenocarcinoma

Benign:3

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 13, 2024	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. -
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. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 10, 2014	- -
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. -

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.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 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

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

CDH1, EXON4, c.531+10G>C, p.?, Heterozygous, BenignrnThe CDH1 c.531+10G>C variant was identified in 7 of 194 proband chromosomes (frequency: 0.036) from individuals or families with gastric cancer and colorectal cancer, but the variant was classified as a benign polymorphism in these studies (Berx 1997, Oliveira 2002, Verma 2001). The variant was also identified in dbSNP (rs: rs33963999) as other, ClinVar 5x (classified as benign by multiple submitters), and the Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, MutDB, or Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 10752 of 276938 chromosomes at a frequency of 0.0388 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Finnish) in 1496 (42 homozygous) of 25776 chromosomes (freq: 0.058), European (Non-Finnish) in 6956 (196 homozygous) of 126510 chromosomes (freq: 0.055), Ashkenazi Jewish* in 404 (11 homozygous) of 10146 chromosomes (freq: 0.04), Other in 245 (8 homozygous) of 6458 chromosomes (freq: 0.038), Latino in 750 (13 homozygous) of 34410 chromosomes (freq: 0.022), South Asian in 665 (12 homozygous) of 30780 chromosomes (freq: 0.022). 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 this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.55

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