chr16-68833444-G-A

Position:

chr16-68833444-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_SupportingPVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.2594G>A p.(Trp865Ter) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region and is downstream of the most 3' pathogenic variant, c.2506G>T p.(Glu836Ter), PVS1_Moderate. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396472624/MONDO:0007648/007

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH1
NM_004360.5 stop_gained

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 9.94

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 Uncertain_significance. Variant got 3 ACMG points.

PVS1

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

PM2

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.2594G>A	p.Trp865Ter	stop_gained	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.2411G>A	p.Trp804Ter	stop_gained	15/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.1046G>A	p.Trp349Ter	stop_gained	16/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.629G>A	p.Trp210Ter	stop_gained	15/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.2594G>A	p.Trp865Ter	stop_gained	16/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2021	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496819). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDH1 gene (p.Trp865*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the CDH1 protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 04, 2023

The c.2594G>A p.(Trp865Ter) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region and is downstream of the most 3' pathogenic variant, c.2506G>T p.(Glu836Ter), PVS1_Moderate. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

The p.W865* variant (also known as c.2594G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2594. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration occurs at the 3' terminus of theCDH1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 2%, 18 amino acids, of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D

Vest4

0.76

GERP RS

6.2

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