rs1060501215
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004360.5(CDH1):c.377del(p.Pro126ArgfsTer89) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R124R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CDH1
NM_004360.5 frameshift
NM_004360.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.12
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 16-68801877-GC-G is Pathogenic according to our data. Variant chr16-68801877-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 406616.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68801877-GC-G is described in Lovd as [Pathogenic]. Variant chr16-68801877-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.377del | p.Pro126ArgfsTer89 | frameshift_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.377del | p.Pro126ArgfsTer89 | frameshift_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1239del | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1443del | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.377del | p.Pro126ArgfsTer89 | frameshift_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726938
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1461178
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32
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AN XY:
726938
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
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 08, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | PVS1; PS4_Moderate; PM2 (PMID: 30311375) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 406616). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer and breast cancer (PMID: 10433926, 17545690). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro126Argfs*89) 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). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 30, 2017 | - - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 28, 2023 | The c.377delC p.(Pro126Argfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 10433926). 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2021 | The c.377delC pathogenic mutation, located in coding exon 3 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 377, causing a translational frameshift with a predicted alternate stop codon (p.P126Rfs*89). This alteration was identified in a family with early onset gastric cancer and lobular breast cancer (Keller G et al. Am J Pathol, 1999 Aug;155:337-42) as well as in a 35-year-old female with diffuse gastric cancer who had family history of diffuse gastric cancer and lobular and ductal breast cancers (Martínez Valenzuela C et al. Mol Genet Genomic Med, 2020 11;8:e1208). 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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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at