rs1555515210
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5_SupportingPVS1PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.455_465delAGAAGAGAGAC p.(Gln152Leufs) 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658683945/MONDO:0007648/007
Frequency
Consequence
ENST00000261769.10 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.455_465del | p.Gln152LeufsTer12 | frameshift_variant | 4/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.455_465del | p.Gln152LeufsTer12 | frameshift_variant | 4/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1161_-1151del | 5_prime_UTR_variant | 4/16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1365_-1355del | 5_prime_UTR_variant | 4/15 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.455_465del | p.Gln152LeufsTer12 | frameshift_variant | 4/16 | 1 | NM_004360.5 | ENSP00000261769 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2017 | This deletion of 11 nucleotides in CDH1 is denoted c.455_465del11 at the cDNA level and p.Gln152LeufsX12 (Q152LfsX12) at the protein level. The surrounding sequence is AGAC[del11]TGGG. The deletion causes a frameshift which changes a Glutamine to a Leucine at codon 152, and creates a premature stop codon at position 12 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant. - |
Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 09, 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.455_465delAGAAGAGAGAC p.(Gln152Leufs) 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 | Color Diagnostics, LLC DBA Color Health | Apr 17, 2020 | This variant deletes 11 nucleotides in exon 4 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at