chr16-68829784-AT-A

Variant names:

• chr16-68829784-AT-A
• rs786203752
• NM_004360.5:c.2430delT

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PS4 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.2430delT (p.Phe810Leufs*6) 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 upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). 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_Strong, PM2_Supporting, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA197715/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: -0.0370
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 9 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.2430delT	p.Phe810LeufsTer6	frameshift_variant	Exon 15 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2247delT	p.Phe749LeufsTer6	frameshift_variant	Exon 14 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.882delT	p.Phe294LeufsTer6	frameshift_variant	Exon 15 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.465delT	p.Phe155LeufsTer6	frameshift_variant	Exon 14 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2430delT	p.Phe810LeufsTer6	frameshift_variant	Exon 15 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe810Leufs*6) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the CDH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with diffuse gastric cancer and gastric cancer (PMID: 26182300; internal data). ClinVar contains an entry for this variant (Variation ID: 187464). This variant disrupt the cytoplasmic domain of the CDH1 (E-cadherin) protein, including the PIP5K1C and CTNNB1 binding domains (PMID: 22850631, 19268661) which are necessary for E-cadherin function. While functional studies have not been performed to directly test the effect of this variant on CDH1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Jun 15, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Feb 16, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH1 c.2430delT (p.Phe810LeufsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 120568 control chromosomes. c.2430delT has been reported in the literature in at least one individual affected with Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 15 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2430delT pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 2430, causing a translational frameshift with a predicted alternate stop codon (p.F810Lfs*6). This alteration was identified in a proband with a family history of gastric cancer who was diagnosed with diffuse gastric cancer at age 45 (Hansford S et al. JAMA Oncol. 2015 Apr;1(1):23-32). In addition, a mutation resulting in the same stop codon (c.2398delC) has been seen in multiple patients and families with diffuse gastric cancer and lobular breast cancer (Kaurah P et al. JAMA. 2007 Jun;297(21):2360-72; Petridis C et al. Br. J. Cancer. 2014 Feb;110(4):1053-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Apr 30, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of one nucleotide in CDH1 is denoted c.2430delT at the cDNA level and p.Phe810LeufsX6 (F810LfsX6) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATTT[delT]ATTG. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 810, and creates a premature stop codon at position 6 of the new reading frame. This variant has been reported in a family with a diagnosis of Hereditary Diffuse Gastric Cancer (Hansford 2015). We consider this variant to be pathogenic. -

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

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2430delT (p.Phe810Leufs*6) 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 upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). 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_Strong, PM2_Supporting, PS4. -

Familial cancer of breast Pathogenic:1

Feb 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.037
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786203752; hg19: chr16-68863687;