chr16-68833296-A-T

Variant names:

• chr16-68833296-A-T
• rs1555518211
• NM_004360.5:c.2446A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.2446A>T (p.Lys816Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein within the NMD-resistant zone and located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in one family meeting clinical criteria for HDGC (PS4_Supporting; PMID:29798843). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel(Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396471960/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2446A>T	p.Lys816*	stop_gained	Exon 16 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2263A>T	p.Lys755*	stop_gained	Exon 15 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.898A>T	p.Lys300*	stop_gained	Exon 16 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.481A>T	p.Lys161*	stop_gained	Exon 15 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2446A>T	p.Lys816*	stop_gained	Exon 16 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Dec 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is expected to delete the C-terminal portion of the cytoplasmic domain of the CDH1 (E-cadherin) protein, which includes the binding domains for the PIP5K1C (phosphatidylinositol phosphate kinase, type I gamma) and CTNNB1 (beta-catenin) proteins (PMID: 22850631). Loss of these domains is expected to disrupt normal E-cadherin function (PMID: 17261850, 10037790). This suggests that deletion of this region of the CDH1 protein is causative of disease. This variant has not been reported in the literature in individuals with CDH1-related disease. 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.Lys816*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 67 amino acids of the CDH1 protein. -

CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1

Mar 25, 2024

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2446A>T (p.Lys816Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein within the NMD-resistant zone and located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in one family meeting clinical criteria for HDGC (PS4_Supporting; PMID: 29798843). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel(Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting. -

Familial cancer of breast Pathogenic:1

May 14, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 02, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K816* variant (also known as c.2446A>T), located in coding exon 16 of the CDH1 gene, results from an A to T substitution at nucleotide position 2446. This changes the amino acid from a lysine to a stop codon within coding exon 16. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CDH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 67 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the deleted region eliminates the catenin-binding domain, which is important for regulating the stability of cadherin mediated cell-cell adhesion (Ishiyama N et al. Cell. 2010 Apr;141:117-28). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.86
GERP RS		5.0

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

Other links and lift over

dbSNP: rs1555518211; hg19: chr16-68867199;