rs786203752
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004360.5(CDH1):c.2430del(p.Phe810LeufsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CDH1
NM_004360.5 frameshift
NM_004360.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0370
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-68829784-AT-A is Pathogenic according to our data. Variant chr16-68829784-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 187464.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.2430del | p.Phe810LeufsTer6 | frameshift_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2247del | p.Phe749LeufsTer6 | frameshift_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.882del | p.Phe294LeufsTer6 | frameshift_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.465del | p.Phe155LeufsTer6 | frameshift_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2430del | p.Phe810LeufsTer6 | frameshift_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727220
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 15, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2018 | Variant summary: CDH1 c.2430delT (p.Phe810LeufsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 120568 control chromosomes. c.2430delT has been reported in the literature in at least one individual affected with Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupt the cytoplasmic domain of the CDH1 (E-cadherin) protein, including the PIP5K1C and CTNNB1 binding domains (PMID: 22850631, 19268661) which are necessary for E-cadherin function. While functional studies have not been performed to directly test the effect of this variant on CDH1 protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 187464). This premature translational stop signal has been observed in individuals with diffuse gastric cancer and gastric cancer (PMID: 26182300; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe810Leufs*6) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the CDH1 protein. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 1 nucleotide in exon 15 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 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2024 | The c.2430delT pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 2430, causing a translational frameshift with a predicted alternate stop codon (p.F810Lfs*6). This alteration was identified in a proband with a family history of gastric cancer who was diagnosed with diffuse gastric cancer at age 45 (Hansford S et al. JAMA Oncol. 2015 Apr;1(1):23-32). In addition, a mutation resulting in the same stop codon (c.2398delC) has been seen in multiple patients and families with diffuse gastric cancer and lobular breast cancer (Kaurah P et al. JAMA. 2007 Jun;297(21):2360-72; Petridis C et al. Br. J. Cancer. 2014 Feb;110(4):1053-7). 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. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2018 | This deletion of one nucleotide in CDH1 is denoted c.2430delT at the cDNA level and p.Phe810LeufsX6 (F810LfsX6) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATTT[delT]ATTG. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 810, and creates a premature stop codon at position 6 of the new reading frame. This variant has been reported in a family with a diagnosis of Hereditary Diffuse Gastric Cancer (Hansford 2015). We consider this variant to be 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 29, 2023 | The c.2430delT (p.Phe810Leufs*6) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). 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_Strong, PM2_Supporting, PS4. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2023 | - - |
Computational scores
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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