16-68738413-T-TGAG

Position:

chr16-68738413-T-TGAG

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 CDH1 c.163+4_163+6dupAGG variant occurs in the splice donor region of intron 2. This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in the gnomAD database (GRCh37) (http://gnomad.broadinstitute.org). This variant has been observed in more than ten individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000969083.1, SCV000216473.4, SCV000637738.2). In summary, this variant is classified as likely benign based on 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/CA194099/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

CDH1
NM_004360.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.592

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	Effect	MANE	Protein	UniProt
CDH1	NM_004360.5 linkuse as main transcript	c.163+4_163+6dupAGG	splice_region_variant, intron_variant	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 linkuse as main transcript	c.163+4_163+6dupAGG	splice_region_variant, intron_variant		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 linkuse as main transcript	c.-1453+4_-1453+6dupAGG	splice_region_variant, intron_variant		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 linkuse as main transcript	c.-1657+4_-1657+6dupAGG	splice_region_variant, intron_variant		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.163+4_163+6dupAGG	splice_region_variant, intron_variant	1	NM_004360.5	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6 linkuse as main transcript	c.163+4_163+6dupAGG	splice_region_variant, intron_variant	1		ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5 linkuse as main transcript	n.163+4_163+6dupAGG	splice_region_variant, intron_variant	1		ENSP00000454782.1	H3BNC6
CDH1	ENST00000566510.5 linkuse as main transcript	n.163+4_163+6dupAGG	splice_region_variant, intron_variant	5		ENSP00000458139.1	H3BVI7

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000134

AC:

AN:

149510

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

79410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000936

Gnomad SAS exome

AF:

0.0000451

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000506

AC:

AN:

1384118

Hom.:

Cov.:

AF XY:

0.00000440

AC XY:

AN XY:

681940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000509

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000523

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 22, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

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 CDH1 c.163+4_163+6dupAGG variant occurs in the splice donor region of intron 2. This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in the gnomAD database (GRCh37) (http://gnomad.broadinstitute.org). This variant has been observed in more than ten individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000969083.1, SCV000216473.4, SCV000637738.2). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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