rs1555514429
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004360.5(CDH1):c.261del(p.Arg87SerfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R87R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CDH1
NM_004360.5 frameshift
NM_004360.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.74
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 16-68801765-AG-A is Pathogenic according to our data. Variant chr16-68801765-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 463772.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.261del | p.Arg87SerfsTer30 | frameshift_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.261del | p.Arg87SerfsTer30 | frameshift_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1355del | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1559del | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.261del | p.Arg87SerfsTer30 | frameshift_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change creates a premature translational stop signal (p.Arg87Serfs*30) 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: 463772). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 08, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 04, 2023 | The c.261delG p.(Arg87Serfs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). 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 (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2023 | The c.261delG pathogenic mutation, located in coding exon 3 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 261, causing a translational frameshift with a predicted alternate stop codon (p.R87Sfs*30). This alteration was identified in multiple individuals diagnosed with lobular breast cancer (Ambry internal data; Gamble LA et al. JAMA Surg, 2022 Jan;157:18-22). 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at