rs1131690822
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004360.5(CDH1):c.2490dup(p.Leu831AlafsTer4) 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 Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L830L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CDH1
NM_004360.5 frameshift
NM_004360.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.221
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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-68833339-T-TG is Pathogenic according to our data. Variant chr16-68833339-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428634.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.2490dup | p.Leu831AlafsTer4 | frameshift_variant | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2307dup | p.Leu770AlafsTer4 | frameshift_variant | 15/15 | ||
CDH1 | NM_001317185.2 | c.942dup | p.Leu315AlafsTer4 | frameshift_variant | 16/16 | ||
CDH1 | NM_001317186.2 | c.525dup | p.Leu176AlafsTer4 | frameshift_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2490dup | p.Leu831AlafsTer4 | frameshift_variant | 16/16 | 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: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Glu836*) have been determined to be pathogenic (PMID: 29798843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428634). This premature translational stop signal has been observed in individuals with diffuse gastric cancer (PMID: 29798843; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu831Alafs*4) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) 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 30, 2023 | The c.2490dupG (p.Leu831AlafsTer4) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and upstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in a family meeting HDGC criteria (PS4_Supporting; SCV000580713.3). In summary, the clinical significance of this variant is likely 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, Supporting, PM2_Supporting - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 31, 2015 | The c.2490dupG variant, located in coding exon 16 of the CDH1 gene, results from a duplication of G at nucleotide position 2490, and causes a translational frameshift with a predicted alternate stop codon (p.L831Afs*4). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 52 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, the deleted region eliminates the catenin-binding domain, which is important for regulating the stability of cadherin mediated cell-cell adhesion (Ishiyama N et al. Cell 2010 Apr; 141(1):117-28). In addition, this alteration was previously seen in a patient diagnosed with diffuse gastric cancer at 31 (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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