rs786201045

chr16-68812132-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_004360.5(CDH1):c.1009_1010del variant causes a splice acceptor change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 splice_acceptor
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 7.39

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.048320122 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.2, offset of 0 (no position change), new splice context is: ttgtgtcgatctctctgcAGttt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 16-68812132-CAG-C is Pathogenic according to our data. Variant chr16-68812132-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 183727.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1009_1010del		splice_acceptor_variant		ENST00000261769.10
CDH1	NM_001317184.2	c.1009_1010del		splice_acceptor_variant
CDH1	NM_001317185.2	c.-607_-606del		splice_acceptor_variant
CDH1	NM_001317186.2	c.-811_-810del		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1009_1010del		splice_acceptor_variant		1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3 Other:1

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	Invitae	Aug 06, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of hereditary diffuse gastric cancer and has been described as disease causing (PMID: 26182300). This variant is also known as c.1009-2delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 183727). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser337Phefs*12) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 12, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-07-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2017	The c.1009_1010delAG pathogenic mutation, located in coding exon 8 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 1009 to 1010, causing a translational frameshift with a predicted alternate stop codon (p.S337Ffs*12). This mutation has been reported in a cohort of French CDH1 mutation carriers (Benusiglio PR et al. J. Med. Genet. 2015 Aug;52:563-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 17, 2023	This variant deletes 2 nucleotides in exon 8 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 been observed in an individual affected with lobular breast cancer before the age of 55 years (PMID: 36436516) and in an individual affected with gastric cancer at age 54 with a family history of the disease (PMID: doi:10.1007/s12672-023-00623-4). 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. -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 25, 2023

The c.1009_1010delAG (p.Ser337Phefs) 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://https://gnomad.broadinstitute.org/). Two probands meet HDGC phenotype criteria (PS4_Moderate; SCV000212776.4). 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, PM2_Supporting, PS4_Moderate, PM5_Supporting. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 5
DS_AL_spliceai		1.0		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786201045; hg19: chr16-68846035;