Associated disorders

The BAP1 gene is associated with autosomal dominant BAP1 tumor predisposition syndrome (MedGen UID: 482122).

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The BAP1 gene encodes a type of deubiquitinating enzyme, and forms a tumor-suppressor complex with BRCA1 and BARD1. The BAP1 gene also interacts with the ASXL1 gene, which is involved in stem cell pluripotency and other developmental processes.

BAP1 hereditary cancer predisposition syndrome
MedGen UID: 482122

Clinical condition
BAP1 hereditary cancer predisposition syndrome is a recently described condition associated with an increased risk for multiple cancers, including uveal melanoma, malignant mesothelioma, cutaneous melanoma, and renal cell carcinoma.

Not everyone with a BAP1 pathogenic variant will manifest symptoms. It has been reported that up to 85% will develop cancer by age 65 (PMID: 26096145). A review article inclusive of 57 families with 174 individuals reported to carry a pathogenic BAP1 variant found 31% of affected individuals to have uveal melanoma, 13% to have cutaneous melanoma, 10% to have renal cell carcinoma, and 22% to have malignant mesothelioma (PMID: 26096145, 23684012).

When malignancies occur in a setting of hereditary BAP1 pathogenic variants, they tend to have an earlier age of onset, be more aggressive, and metastasize more often compared to individuals with sporadic versions of the same types of cancer (PMID: 26140217, 26096145, 22935333 ). The exception to this is malignant mesothelioma, which is typically less aggressive and has a more favorable outcome in individuals with BAP1 hereditary cancer predisposition syndrome (PMID: 26140217, 26096145, 22935333).

Most BAP1-affected individuals also develop multiple benign cutaneous melanocytic neoplasms resembling atypical Spitz tumors and dermal nevi, but these neoplasms are clinically, histologically, and genetically distinct. A Spitz tumor is an uncommon benign melanocytic lesion composed of large epithelioid and/or spindled cells. It typically presents in childhood or adolescence as a dome-shaped, pink-red papule, histologically resembling a melanoma but without the typical aggressive clinical behavior associated with adult melanoma (PMID: 26096145).

BAP1-related dermal lesions typically present in childhood or adolescence, often with more developing over a lifetime. The lesions are considered clinically stable, with a low risk of malignancy; however, there have been reports of transformation to malignant melanoma and basal cell carcinoma (PMID: 25225168). There is currently no agreement among pathologists on the classification or nomenclature of these distinctive BAP1 dermal tumors. They may be referred to as combined nevi, melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), atypical Spitz tumors (AST), combined Spitz tumors, or halo Spitz tumors (Barnhill RL. Gennery A. Spitzoid melanocytic neoplasms (Spitz nevus and atypical Spitz tumors). In: UpToDate, Tsao (Ed), UpToDate, Waltham, MA. Accessed July 2015).

BAP1-related lesions may be used to screen individuals for BAP1 hereditary cancer predisposition syndrome, as up to 72% of individuals with this condition have one or more atypical Spitz-like tumors. The tumors are characterized by biallelic inactivation of BAP1 and frequent BRAFV600E mutation, both of which can be reliable markers for aiding in the diagnosis. They typically occur earlier than the other associated malignancies, enabling identification of at-risk individuals, genetic testing, and implementation of surveillance protocols (PMID: 26140217, 26096145).

BAP1 also has preliminary evidence of an association with meningioma, and is therefore available as a “preliminary evidence” gene on the Invitae Nervous System/Brain Cancer Panel (PMID: 26140217, 21941004). preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary evidence genes.

Gene information
This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) and acts as a tumor suppressor. The enzyme may also be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics ( Gene. Gene ID: 8314. Accessed September 2015). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

BAP1 hereditary cancer predisposition syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant in BAP1 has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Although many cases are inherited from a parent, some occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in BAP1 has a 50% risk of passing that variant on to offspring.

There are no established screening or surveillance guidelines for individuals with a pathogenic BAP1 variant, but management recommendations have recently been proposed (PMID: 26096145):

  • annual physical examinations
  • the von Hippel-Lindau syndrome protocol for assessing renal cancer (yearly abdominal ultrasound, MRI every 2 years)

for the risk of uveal melanoma:
  • annual dilated eye examinations with ophthalmic imaging by an ocular oncologist beginning at age 11
  • high-risk monitoring for metastasis if a uveal melanoma is diagnosed (liver-directed imaging every 3-6 months and pulmonary imaging 1-2 times per year)
  • annual dermatological full-body skin examinations beginning at age 20
  • skin self-exam following ABCDE melanoma characteristics
  • regular use of sun protection
  • BRAF-mutation testing with immunostaining for BAP1 on biopsied specimens if atypical Spitz-like tumors are detected

Despite the lack of formal medical management guidelines associated with this disorder, an individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though the data regarding pathogenic BAP1 are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding this gene are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: October 2015

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
BAP1 NM_004656.3