rs1555517889
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5_SupportingPM2_SupportingPVS1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_004360.5:c.2387_2406del (p.Arg796GlnfsTer4) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID:29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PM5_Supporting, PM2_Supporting. (CDH1 VCEP specifications version 3.1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658798634/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2387_2406del | p.Arg796GlnfsTer4 | frameshift_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2204_2223del | p.Arg735GlnfsTer4 | frameshift_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.839_858del | p.Arg280GlnfsTer4 | frameshift_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.422_441del | p.Arg141GlnfsTer4 | frameshift_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2387_2406del | p.Arg796GlnfsTer4 | frameshift_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2017 | For these reasons, this variant has been classified as Pathogenic. This variant is expected to disrupt the C-terminal portion of the cytoplasmic domain of the CDH1 (E-cadherin) protein, which includes the PIP5K1C (phosphatidylinositol phosphate kinase, type I gamma) binding domain (residues Leu830-Ser847) and the CTNNB1 (beta-catenin) binding domain (residues Val832-Tyr861) (PMID: 22850631). Although functional studies have not been performed for this particular variant, loss of these domains is expected to disrupt normal CDH1 function. This suggests that disruption of this region of the CDH1 protein is causative of disease. This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDH1 gene (p.Arg796Glnfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 87 amino acids of the CDH1 protein. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 02, 2023 | The NM_004360.5:c.2387_2406del (p.Arg796GlnfsTer4) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PM5_Supporting, PM2_Supporting. (CDH1 VCEP specifications version 3.1) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at