rs761753486

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004360.5(CDH1):​c.570C>A​(p.Tyr190Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.694
Variant links:
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]

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ACMG classification

Classification made for transcript

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 16-68808731-C-A is Pathogenic according to our data. Variant chr16-68808731-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1387468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.570C>A p.Tyr190Ter stop_gained 5/16 ENST00000261769.10 NP_004351.1
CDH1NM_001317184.2 linkuse as main transcriptc.570C>A p.Tyr190Ter stop_gained 5/15 NP_001304113.1
CDH1NM_001317185.2 linkuse as main transcriptc.-1046C>A 5_prime_UTR_variant 5/16 NP_001304114.1
CDH1NM_001317186.2 linkuse as main transcriptc.-1250C>A 5_prime_UTR_variant 5/15 NP_001304115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.570C>A p.Tyr190Ter stop_gained 5/161 NM_004360.5 ENSP00000261769 P1P12830-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingEuropean Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of PortoAug 01, 2022PVS1; PS4_Supporting; PM2 (PMID: 30311375) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 29, 2021For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CDH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr190*) 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). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 08, 2021The p.Y190* pathogenic mutation (also known as c.570C>A), located in coding exon 5 of the CDH1 gene, results from a C to A substitution at nucleotide position 570. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Benign
0.058
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.88
D
MutationTaster
Benign
1.0
A;A
Vest4
0.95
GERP RS
-0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68842634; API