rs1555515284

Variant names:

• chr16-68808815-GC-G
• rs1555515284
• NM_004360.5:c.656delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5_Supporting PVS1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.656del p.(Pro219fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760825.3). Therefore, 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_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658683948/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 3.15
• Publications: 0 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 11 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.656delC	p.Pro219LeufsTer31	frameshift	Exon 5 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.656delC	p.Pro219LeufsTer31	frameshift	Exon 5 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.-960delC		5_prime_UTR	Exon 5 of 16	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.656delC	p.Pro219LeufsTer31	frameshift	Exon 5 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.656delC	p.Pro219LeufsTer31	frameshift	Exon 5 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.727delC		non_coding_transcript_exon	Exon 4 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Sep 07, 2017

GeneID Lab - Advanced Molecular Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 23, 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.Pro219Leufs*31) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 488647). For these reasons, this variant has been classified as Pathogenic.

Jun 09, 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.

not provided Pathogenic:2

Mar 01, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 09, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with personal and family history of gastric cancer in the literature (Adib et al., 2022); This variant is associated with the following publications: (PMID: 34949788)

not specified Pathogenic:1

Jan 14, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDH1 c.656delC; p.Pro219fs variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic/pathogenic in ClinVar (Variation ID: 488647). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function CDH1 variants are considered to be pathogenic (Brooks-Wilson 2004, Guilford 1999). Based on available information, the c.656delC variant is considered to be pathogenic. REFERENCES Brooks-Wilson AR et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004 Jul;41(7):508-17. Guilford PJ et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999;14(3):249-55.

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

Aug 25, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.656del p.(Pro219fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760825.3). Therefore, 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_Supporting, PM5_Supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=1/199	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: rs1555515284; hg19: chr16-68842718;