rs34939176

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004360.5(CDH1):c.2164+17dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,543,948 control chromosomes in the GnomAD database, including 1,420 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.031 ( 120 hom., cov: 31)

Exomes 𝑓: 0.039 ( 1300 hom. )

Consequence

CDH1
NM_004360.5 intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.266

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 Benign. Variant got -16 ACMG points.

BP6

Variant 16-68823641-C-CA is Benign according to our data. Variant chr16-68823641-C-CA is described in ClinVar as [Benign]. Clinvar id is 259292.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.2164+17dup	intron_variant	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.1981+17dup	intron_variant
CDH1	NM_001317185.2 linkuse as main transcript	c.616+17dup	intron_variant
CDH1	NM_001317186.2 linkuse as main transcript	c.199+17dup	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.2164+17dup		intron_variant		1	NM_004360.5	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4720

AN:

152110

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0710

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.0749

Gnomad SAS

AF:

0.0581

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0336

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0478

AC:

11608

AN:

243006

Hom.:

418

AF XY:

0.0465

AC XY:

6137

AN XY:

131948

show subpopulations

Gnomad AFR exome

AF:

0.00805

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.0786

Gnomad SAS exome

AF:

0.0657

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0387

AC:

53830

AN:

1391720

Hom.:

1300

Cov.:

AF XY:

0.0391

AC XY:

27213

AN XY:

696346

show subpopulations

Gnomad4 AFR exome

AF:

0.00614

Gnomad4 AMR exome

AF:

0.0979

Gnomad4 ASJ exome

AF:

0.0265

Gnomad4 EAS exome

AF:

0.0753

Gnomad4 SAS exome

AF:

0.0608

Gnomad4 FIN exome

AF:

0.0246

Gnomad4 NFE exome

AF:

0.0351

Gnomad4 OTH exome

AF:

0.0374

GnomAD4 genome

AF:

0.0311

AC:

4731

AN:

152228

Hom.:

120

Cov.:

AF XY:

0.0317

AC XY:

2360

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00669

Gnomad4 AMR

AF:

0.0710

Gnomad4 ASJ

AF:

0.0309

Gnomad4 EAS

AF:

0.0741

Gnomad4 SAS

AF:

0.0580

Gnomad4 FIN

AF:

0.0202

Gnomad4 NFE

AF:

0.0336

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0312

Hom.:

Bravo

AF:

0.0342

Asia WGS

AF:

0.0850

AC:

296

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

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	Apr 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

Hereditary diffuse gastric adenocarcinoma

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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.2164+17dup variant has an allele frequency of 0.1034 (10%, 3634/35146 alleles, 197 homozygotes) in the Latino 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 31, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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