chr16-68738307-G-A

Position:

chr16-68738307-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4_ModeratePM5_SupportingPVS1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.59G>A (p.Trp20*) variant is predicted to result in a premature stop codon in exon 2 that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID:10072428, 26182300). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280996/MONDO:0007648/007

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDH1
ENST00000261769.10 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 1.11

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 Pathogenic. Variant got 12 ACMG points.

PVS1

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

PS4

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

PM2

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

PM5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH1	NM_004360.5 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained	2/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.-1557G>A		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-1761G>A		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained	2/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1
CDH1	ENST00000422392.6 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained	2/15	1		ENSP00000414946		P12830-2
CDH1	ENST00000566612.5 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained, NMD_transcript_variant	2/15	1		ENSP00000454782
CDH1	ENST00000566510.5 linkuse as main transcript	c.59G>A	p.Trp20Ter	stop_gained, NMD_transcript_variant	2/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398052

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689674

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:4

Pathogenic, 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	PVS1; PS4_Moderate; PM2 (PMID: 30311375) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been observed in several individuals affected with diffuse gastric cancer (PMID: 10072428, 28688938,¬†18788075). ClinVar contains an entry for this variant (Variation ID: 12239). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp20*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 08, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 29, 2023

The c.59G>A (p.Trp20*) variant is predicted to result in a premature stop codon in exon 2 that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 10072428, 26182300). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.18

MutationTaster

Benign

1.0

A;A

Vest4

0.88

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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