rs876658261

chr16-68815680-TCCGAGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004360.5(CDH1):c.1488_1494del(p.Glu497LeufsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S496S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 9.60

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68815680-TCCGAGGA-T is Pathogenic according to our data. Variant chr16-68815680-TCCGAGGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 229907.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68815680-TCCGAGGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1488_1494del	p.Glu497LeufsTer23	frameshift_variant	10/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1305_1311del	p.Glu436LeufsTer23	frameshift_variant	9/15
CDH1	NM_001317185.2	c.-61_-55del		5_prime_UTR_variant	10/16
CDH1	NM_001317186.2	c.-332_-326del		5_prime_UTR_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1488_1494del	p.Glu497LeufsTer23	frameshift_variant	10/16	1	NM_004360.5	P1
	ENST00000563916.1	n.264-28_264-22del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 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	Myriad Genetics, Inc.	Jun 14, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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_Supporting; PM2 (PMID: 30311375) -
not provided, no classification provided	phenotyping only	GenomeConnect - No Stomach For Cancer	-	Variant interpreted as Pathogenic and reported on 01-05-2015 by lab or GTR ID 61756. GenomeConnect - No Stomach for Cancer 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been reported in an individual affected with diffuse gastric cancer (PMID: 10477433). This variant is also known as 1487del7 in the literature. ClinVar contains an entry for this variant (Variation ID: 229907). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu497Leufs*23) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 26, 2019	This variant alters the translational reading frame of the CDH1 mRNA and causes the premature termination of CDH1 protein synthesis. This variant has been reported in individuals with diffuse gastric and breast cancer in the published literature (PMID: 10477433 (1999), 27878467 (2017)). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2019	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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30935944, 26182300, 19725995, 19168852, 22225527, 15457549, 27878467, 10477433) -

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.1488_1494delCGAGGAC p.(Glu497Leufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is present in <1/50,000 alleles 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; PMID: 10477433). 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_Supporting, PM5_Supporting. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 11, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2022

The c.1488_1494delCGAGGAC pathogenic mutation, located in coding exon 10 of the CDH1 gene, results from a deletion of 7 nucleotides at nucleotide positions 1488 to 1494, causing a translational frameshift with a predicted alternate stop codon (p.E497Lfs*23). This mutation has been reported in an individual with diffuse gastric cancer diagnosed at age 31 (Guilford PJ et al. Hum. Mutat. 1999;14:249-55). It has also been reported in a patient with lobular breast cancer diagnosed at age 53, who had a family history of lobular breast cancer but no reported family history of gastric cancer (Jacobs MF et al. Gastroenterology. 2019 Jul;157:87-96). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658261; hg19: chr16-68849583;