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BAP1
BRCA1 associated deubiquitinase 1
The BAP1 gene provides instructions for a protein that acts as a deubiquitinase, playing a crucial role in cell growth, DNA repair, and tumour suppression. BAP1 is a vital gene involved in maintaining cellular health and preventing uncontrolled cell proliferation.
BAP1 is located on the short (p) arm of chromosome 3, at band 3p21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The BAP1 gene, also known as BRCA1 associated deubiquitinase 1, encodes a protein that acts as a tumour suppressor by helping to prevent abnormal cellular growth and replication. It is classified as an autosomal dominant gene, meaning that inheriting one altered copy can increase disease risk. This gene is vital for cellular health, and variations in BAP1 are linked to a heightened susceptibility to several types of tumours. BAP1 is recognised as part of the American College of Medical Genetics and Genomics (ACMG) Secondary Findings list version 3.2, reflecting its clinical significance.
What the gene does
The BAP1 gene encodes the ubiquitin carboxyl-terminal hydrolase BAP1 protein, which operates as a deubiquitinase. This enzyme removes ubiquitin molecules from other proteins. Ubiquitin tagging is a key regulatory mechanism that can affect a protein's activity, its interactions with other cellular components, and its degradation. When BAP1 removes ubiquitin from target proteins, it alters their functional state and stability within the cell. This regulatory activity influences several fundamental cellular processes, including cell growth and division (proliferation), DNA damage repair, and the cell cycle progression. As a tumour suppressor, the BAP1 protein helps to prevent cells from growing and dividing too rapidly or in an uncontrolled manner, thereby protecting against tumour formation. Research suggests BAP1 also participates in controlling gene activity and coordinating DNA repair mechanisms, though the precise molecular pathways remain an area of ongoing investigation.
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Chromosome location
The BAP1 gene is located on the short (p) arm of chromosome 3, specifically at position 3p21.1. This precise genomic address helps scientists identify and study the gene within the human genome.
Protein structure
The BAP1 protein is composed of 729 amino acids and contains several distinct domains and motifs essential for its biological activity. Its deubiquitinase function is centred within a UCH catalytic domain, spanning amino acids 4-235, which contains an Arg-finger motif at positions 56-60. The protein features multiple disordered regions, including those at amino acids 301-351, 372-435, 464-524, 575-623, and 703-729. Key interaction sites include an HBM-like motif (amino acids 363-366), a region that binds BRCA1 (amino acids 596-721), and another involved in interaction with YY1 (amino acids 642-686). Additionally, BAP1 possesses a coiled coil region (amino acids 636-656), a ULD domain (amino acids 670-698), and a region (amino acids 699-701) that interacts with nucleosomal DNA, forming a DNA clamp with ASXL1. Nuclear localisation is facilitated by a classical bipartite NLS motif (amino acids 699-722) and a non-classical PY-NLS motif (amino acids 717-724). A positively charged C-terminal extension (CTE) is also present at amino acids 713-729.
Key variants
Genetic variations within the BAP1 gene can alter the protein's structure or function, leading to impaired tumour suppressor activity. These changes, known as pathogenic variants, can increase an individual's predisposition to certain types of cancer. While some variants may have a clear impact, others might have a more subtle effect, and their clinical significance is continuously being evaluated through research.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1006del | p.Val335_Val336insTer | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1063C>T | p.Gln355Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.106C>T | p.Gln36Ter | Pathogenic | ★★☆☆ | BAP1-related tumor predisposition syndrome |
c.1088del | p.Asn363fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1153C>T | p.Arg385Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1169dup | p.Pro391fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1174C>T | p.Gln392Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1178del | p.Gln393fs | Pathogenic | ★★☆☆ | BAP1-related tumor predisposition syndrome |
c.1182C>G | p.Tyr394Ter | Pathogenic | ★★☆☆ | BAP1-related tumor predisposition syndrome |
c.1184C>G | p.Ser395Ter | Pathogenic/Likely pathogenic | ★★☆☆ | BAP1-related tumor predisposition syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the BAP1 gene cause BAP1 tumour predisposition syndrome. Individuals with this inherited condition have a significantly increased risk of developing various benign and malignant tumours. These can include atypical Spitz tumours of the skin, cutaneous melanoma, and basal cell carcinomas. BAP1 is also linked to melanoma and cholangiocarcinoma. In addition, somatic (non-inherited) mutations in BAP1 have been identified in sporadic cases of uveal melanoma, malignant mesothelioma, and clear cell renal cell carcinoma in individuals without a family history of these cancers.
Inheritance pattern
Conditions caused by pathogenic BAP1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The BAP1 gene is recognised within the UK's NHS Genomic Medicine Service and is listed on several crucial PanelApp panels. It is green-listed for 'Adult solid tumours cancer susceptibility', 'Adult solid tumours for rare disease', 'BAP1 associated tumour predisposition syndrome (R422)', 'Childhood solid tumours', 'DDG2P', 'Early onset or syndromic epilepsy (R59)', 'Familial melanoma (R254)', 'Inherited renal cancer (R224)', 'Intellectual disability (R29)', 'Melanoma pertinent cancer susceptibility', and 'Pigmentary skin disorders (R236)'. This indicates that BAP1 testing is considered clinically appropriate for these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the BAP1 gene?
The BAP1 gene encodes a deubiquitinase enzyme that removes ubiquitin from other proteins. This action is crucial for regulating protein stability and function, playing key roles in cell growth, DNA repair, and acting as a tumour suppressor.
What is BAP1 tumour predisposition syndrome?
BAP1 tumour predisposition syndrome is an inherited condition caused by pathogenic variants in the BAP1 gene. It increases an individual's risk of developing various benign and malignant tumours, including specific skin cancers such as atypical Spitz tumours and cutaneous melanoma.
How is BAP1 related to cancer?
BAP1 acts as a tumour suppressor gene. When functioning correctly, it helps prevent uncontrolled cell growth and division. Pathogenic variants in BAP1 can impair this protective function, leading to an increased susceptibility to several types of cancer.
References
- Royer-Bertrand B, Torsello M, Rimoldi D. Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing. American journal of human genetics. 2016. PMID: 27745836
- Kumar R, Taylor M, Miao B. BAP1 has a survival role in cutaneous melanoma. The Journal of investigative dermatology. 2015. PMID: 25521456
- Alakus H, Yost SE, Woo B. BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma. Journal of translational medicine. 2015. PMID: 25889843
- Daou S, Hammond-Martel I, Mashtalir N. The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer. The Journal of biological chemistry. 2015. PMID: 26416890
- Yu H, Pak H, Hammond-Martel I. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America. 2014. PMID: 24347639
- Matatall KA, Agapova OA, Onken MD. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC cancer. 2013. PMID: 23915344
- Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A. BAP1 loss defines a new class of renal cell carcinoma. Nature genetics. 2012. PMID: 22683710
- Eletr ZM, Wilkinson KD. An emerging model for BAP1's role in regulating cell cycle progression. Cell biochemistry and biophysics. 2011. PMID: 21484256
- Ventii KH, Devi NS, Friedrich KL. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer research. 2008. PMID: 18757409
- Jensen DE, Proctor M, Marquis ST. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998. PMID: 9528852