rs869025212
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004656.4(BAP1):c.1717delC(p.Leu573TrpfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004656.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BAP1 | NM_004656.4 | c.1717delC | p.Leu573TrpfsTer3 | frameshift_variant | Exon 13 of 17 | ENST00000460680.6 | NP_004647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
BAP1-related tumor predisposition syndrome Pathogenic:5
This mutation (deletion of one nucleotide in the BAP1 gene) was identified in a male patient with familial history of melanoma and mesothelioma -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Leu573Trpfs*3) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mesothelioma and uveal melanoma (PMID: 21874000, 25687217, 26683624). This variant is also known as 1832delC. ClinVar contains an entry for this variant (Variation ID: 221278). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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The c.1717delC pathogenic mutation, located in coding exon 13 of the BAP1 gene, results from a deletion of one nucleotide at nucleotide position 1717, causing a translational frameshift with a predicted alternate stop codon (p.L573Wfs*3). This mutation has been reported in multiple kindreds with malignant mesothelioma, uveal melanoma, and/or other BAP-1 associated cancers (Cebulla CM et al. Ophthalmic Genet. 2015 Jun;36:126-31; Ohar JA et al. Cancer Res. 2016 Jan;76:206-15; Testa JR et al. Nat. Genet. 2011 Oct;43:1022-5; Carbone M et al. PLoS Genet. 2015 Dec;11:e1005633; Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11; Haugh AM et al. JAMA Dermatol. 2017 Oct;153:999-1006; Hassan R et al. Proc Natl Acad Sci U S A 2019 04;116(18):9008-9013). 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant deletes 1 nucleotide in exon 13 of the BAP1 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 been reported in individuals affected with uveal melanoma, malignant mesothelioma, and melanocytic BAP1-mutated atypical intradermal tumors (MBAITs; PMID: 21874000, 25687217, 26683624, 26719535, 28793149). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:2
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed frequently in unrelated patients with BAP1-associated malignancy in published literature and described as a European founder variant (PMID: 26683624, 25687217, 26719535, 31206729, 32002398); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32782288, 21874000, 25687217, 26556299, 27813512, 24705312, 28793149, 31206729, 26748926, 26096145, 24855403, 32547381, 26719535, 30883995, 34628055, 30975761, 37556141, 36513904, 32002398, 26683624) -
DNA sequence analysis of the BAP1 gene demonstrated a single base pair deletion in exon 13, c.1717del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon three amino acids downstream of the change, p.Leu573Trpfs*3. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BAP1 protein with potentially abnormal function. The c.1717del sequence change has not been described in population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in individual with BAP1-related tumors and cancers (PMID: 32002398, 26719535, 31206729, 28793149, 26683624, 21874000, 25687217). Collectively, these evidences indicated this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively. -
BAP1 Cancer Syndrome Pathogenic:1
We found 100% penetrance of at least one cancer type in every individual carrying this variant. Our results indicate that this variant has a high prognostic significance. -
Melanoma, uveal, susceptibility to, 2 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at