NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

BAP1 Tumor Predisposition Syndrome

Synonyms: BAP1 Cancer Syndrome; BAP1-TPDS; Cutaneous/Ocular Melanoma, Atypical Melanocytic Proliferations, and Other Internal Neoplasms (COMMON Syndrome)

, MS,LGC, MSW, , BS, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for the specific skin lesion – atypical Spitz tumors – and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), clear cell renal cell carcinoma (ccRCC), and basal cell carcinoma (BCC). Affected individuals can have more than one type of primary cancer. In general the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM that occurs in the general population. However, because of the limited number of families reported to date, the penetrance, natural history, and frequencies of the BAP1-associated tumors are yet to be determined.

Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, cholangiocarcinoma, non-small cell lung adenocarcinoma (NSCLC), meningioma, and neuroendocrine carcinoma.

Diagnosis/testing.

The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing.

Management.

Treatment of manifestations: The treatments for BAP1-TPDS tumors are those used in standard practice. UM: Because of the increased aggressiveness of BAP1-related uveal melanoma, all uveal melanomas should be managed as the more aggressive class 2 or monosomy 3 tumors. MMe is highly refractory to conventional therapies including aggressive surgical intervention and multimodality strategies; thus, a cure is unlikely.

Prevention of primary manifestations: UM: avoid arc-welding. No data exist regarding benefit of sunglasses for reduction of UM risk. MMe: avoid asbestos exposure and smoking. CM and BCC: limit sun exposure, use sunscreen and protective clothing, and have regular dermatologic examinations.

Surveillance: UM: yearly dilated eye examinations and imaging by an ocular oncologist beginning around age 11 years. MMe: No screening modalities exist; however, annual physical examination is recommended. If an abdominal MRI is to be performed as recommended for ccRCC, consider evaluation of the peritoneum and pleura as well. Although some physicians recommend spiral chest CT for asymptomatic persons with a history of exposure to asbestos, others do not, given the possible increased risk of cancer from radiation exposure. CM, basal cell carcinoma, ASTs: Annual full-body dermatologic examinations beginning around age 20 years. ccRCC: annual abdominal ultrasound examination; consider annual urinalysis and abdominal MRI every two years.

Agents/circumstances to avoid: see Prevention of primary manifestations.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of screening and preventive measures.

Genetic counseling.

BAP1-TPDS is inherited in an autosomal dominant manner. To date, most individuals diagnosed with BAP1-TPDS have an affected parent; the proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown. Each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant; however, penetrance appears to be incomplete and the types of BAP1-related tumors can vary among different members of the same family. Once the germline BAP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for BAP1-TPDS and preimplantation genetic diagnosis are possible.

Diagnosis

No diagnostic criteria have been published for the BAP1 tumor predisposition syndrome (BAP1-TPDS).

Suggestive Findings

BAP1 tumor predisposition syndrome (BAP1-TPDS) should be suspected in an individual who has EITHER of the following:

  • Two or more confirmed BAP1-TPDS tumors*
    OR
  • One BAP1-TPDS tumor and a first- or second-degree relative with a confirmed BAP1-TPDS tumor*

* Excluding two basal cell cancers and/or cutaneous melanomas, given their high frequency in the general population

Confirmed BAP1-TPDS tumors include the following (in descending order of likelihood):

  • Atypical Spitz tumors (ASTs), which may be the most common manifestation of BAP1-TPDS, and may result in the initial identification of a proband. ASTs are skin-colored to reddish-brown, averaging 5 mm in diameter; the histologic findings are between those of a Spitz nevus and a melanoma. Both copies of BAP1 are inactivated leading to loss of staining for the BAP1 protein on immunohistochemistry.
  • Uveal (eye) melanoma
  • Malignant mesothelioma (MMe)
  • Cutaneous melanoma
  • Clear cell renal cell carcinoma (ccRCC)
  • Basal cell carcinoma

Unconfirmed tumors (with conflicting evidence regarding inclusion in the BAP1-TPDS tumor spectrum) include the following (in alphabetic order):

  • Breast cancer
  • Cholangiocarcinoma
  • Meningioma
  • Neuroendocrine tumors
  • Non-small cell lung adenocarcinoma (NSCLC)
  • Thyroid cancer

Establishing the Diagnosis

The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing or use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of BAP1 is performed. To date, no published data exist regarding the benefit (or lack thereof) of doing gene-targeted deletion/duplication analysis if no BAP1 pathogenic variant is found on sequence analysis.
  • A multi-gene panel that includes BAP1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

Table 1.

Molecular Genetic Testing Used in BAP1 Tumor Predisposition Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
BAP1Sequence analysis 3All variants reported to date 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available. Using MLPA, no BAP1 exon or multiexon deletions/duplications were identified in 20 individuals with uveal melanoma and a family history of uveal melanoma or in ten individuals with uveal melanoma and a personal or family history of renal cell carcinoma [M Abdel-Rahman, unpublished data].

Clinical Characteristics

Clinical Description

BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a number of cancers and a specific skin lesion (atypical Spitz tumors). Affected individuals can have more than one type of primary cancer [Testa et al 2011, Njauw et al 2012, Aoude et al 2013b, Cheung et al 2015, Ohar et al 2016, Rai et al 2016].

Because of the limited number of families reported to date and because of the ascertainment bias of the interests of the research groups focusing on uveal melanoma, malignant mesothelioma, and cutaneous melanoma, the penetrance and frequencies of the various BAP1-associated tumors are yet to be determined. It has been well established, however, that the following tumor types are associated with BAP1-TPDS.

Atypical Spitz tumors (ASTs). Wiesner et al [2012] categorized these skin lesions as “atypical Spitz tumors”; the authors agree that this is the most appropriate designation (see Nomenclature for other terms used to describe these tumors).

Uveal melanoma (UM) is the cancer most commonly reported in persons with BAP1-TPDS (31%), and the cancer with the earliest reported age of diagnosis (age 16 years) [Rai et al 2016].

Median age of onset of UM in persons with BAP1-TPDS is 51 years, which is younger than the onset of UM in the general population (62 years). The tumors are generally more aggressive class 2 (i.e., high metastatic risk) tumors with higher risk for metastasis and reduced survival [Njauw et al 2012, Rai et al 2016]. In one study, mean length of survival in persons whose uveal melanoma tumor lacked BAP1 expression was 4.74 years compared to 9.97 years in persons whose tumors expressed BAP1 [Kalirai et al 2014].

Malignant mesothelioma (MMe) is the second most frequent cancer (22%) identified in BAP1-TPDS [Testa et al 2011, Rai et al 2016].

Two studies [Baumann et al 2015, Ohar et al 2016] have shown that the median age of onset of MMe in individuals with BAP1-TPDS was significantly earlier (55 and 58 years, respectively) than that of sporadic MMe (72 and 68 years, respectively).

Generally, pleural MMe accounts for about 80% and peritoneal MMe constitutes most of the remaining MMe. However, in individuals with BAP1-TPDS the ratio of peritoneal to pleural involvement is significantly higher [Carbone et al 2015, Cheung et al 2015, Ohar et al 2016]. In BAP1-TPDS the majority of peritoneal MMe occurs in women, in contrast to the general population, in which men are more likely to have this tumor type [Rai et al 2016].

In contrast to survival in persons with BAP1-related cutaneous melanoma, uveal melanoma, or renal cell carcinoma, survival in persons with BAP1-related MMe may be significantly longer [de Reyniès et al 2014, Baumann et al 2015, Carbone et al 2015, Ohar et al 2016]; however, to date the data are not consistent [Singhi et al 2016].

Growing evidence suggests that BAP1 pathogenic variants interact with environmental asbestos exposure to increase the risk for MMe [Xu et al 2014, Kadariya et al 2016].

Cutaneous melanoma (CM). First reported in association with BAP1-TPDS in 2011, CM is now known to be the third most common cancer in BAP1-TPDS, occurring in 13% of affected individuals [Wiesner et al 2011]. Multiple primary cutaneous melanomas are common. The median age of onset of CM in BAP1-TPDS is earlier than in the general population (46 vs 58 years). Although it is possible that BAP1-related CM is more aggressive than cutaneous melanoma in the general population, to date the data are inconsistent [Gupta et al 2015, Kumar et al 2015, Rai et al 2016].

Clear cell renal cell carcinoma (ccRCC). Heterozygous BAP1 germline pathogenic variants are specifically associated with an increased risk for ccRCC [Haas & Nathanson 2014]. Median age of ccRCC diagnosis appears to be younger in persons with BAP1-TPDS than in the general population (47 vs 64 years), and length of survival is decreased in persons with BAP1-related ccRCC [Rai et al 2016]. Histology of these tumors is distinct from tumors not associated with pathogenic variants in BAP1, with higher grade at diagnosis and lack of PBRM1 pathogenic variants (which are common in ccRCC not associated with pathogenic variants in BAP1) [Peña-Llopis et al 2012].

Basal cell carcinoma has recently been confirmed as a tumor in the BAP1-TPDS spectrum [de la Fouchardière et al 2015a, Mochel et al 2015, Wadt et al 2015]. Multiple primary basal cell carcinomas are common. Based on limited information, the median age of diagnosis appears to be around 50 years.

Other cancers with some evidence (although inconsistent) supporting inclusion in the BAP1-TPDS spectrum are the following (in alphabetic order):

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations are published for BAP1-TPDS.

Most families (46 of 57) have had a unique BAP1 pathogenic variant; only five recurrent pathogenic variants have been reported [Rai et al 2016] (see Molecular Genetics).

Penetrance

The penetrance of the BAP1-TPDS appears to be high based on the published literature. In their review Rai et al [2016] found that 148/174 (85%) individuals reported with a heterozygous germline BAP1 pathogenic variant had a cancer diagnosis. However, ascertainment biases in favor of both testing and reporting affected versus unaffected individuals may have inflated this figure. For example, in more than half of the reported families only the proband had been tested. Given these biases, an accurate estimate of penetrance cannot be determined at this time.

Nomenclature

Atypical Spitz tumors have also been called the following:

  • Nevoid melanoma-like melanocytic proliferations (NEMMP) [Njauw et al 2012]
  • Melanocytic BAP1-mutated atypical intradermal tumors (MBAITS) [Carbone et al 2012]
  • BAPoma [Author, personal observation]

Prevalence

The prevalence of BAP1-TPDS is unknown. A 2015 review identified 57 published families with 174 individuals with BAP1-TPDS [Rai et al 2016].

The data on the prevalence of BAP1-TPDS in persons with uveal melanoma, mesothelioma, cutaneous melanoma, and familial renal cell carcinoma are limited. The prevalence of BAP1-TPDS in persons with other cancers is unknown.

Of note, in one review 90% of families reported with a germline BAP1 pathogenic variant met the criteria outlined in Suggestive Findings [Rai et al 2016]; whereas germline BAP1 pathogenic variants are rare in unselected series of individuals with one tumor type or families with multiple members with only one tumor type (i.e., uveal melanoma [Abdel-Rahman et al 2011, Turunen et al 2016], mesothelioma [Testa et al 2011], cutaneous melanoma [Aoude et al 2015], or renal cell carcinoma [Farley et al 2013, Popova et al 2013]).

Uveal melanoma. The prevalence of germline BAP1 pathogenic variants in unselected individuals with uveal melanoma is 1%-2% [Aoude et al 2013a]; in contrast, the frequency is 20%-30% in persons with uveal melanoma who have a family history of uveal melanoma [Popova et al 2013, Gupta et al 2015, Turunen et al 2016].

Malignant mesothelioma (MMe). Germline BAP1 pathogenic variants have been identified in 6% (9/153) to 20% (1/5) of individuals with familial mesothelioma [Betti et al 2015, Ohar et al 2016]; however they are rare in simplex cases (i.e., a single occurrence of MMe in a family) [Rusch et al 2014, Betti et al 2015, Sneddon et al 2015, Ohar et al 2016].

Cutaneous melanoma. A germline BAP1 heterozygous missense variant was identified in 0.63% of a population-based cohort of 1109 probands with cutaneous melanoma [Aoude et al 2015].

Differential Diagnosis

Mutation of other genes can be associated with uveal melanoma, malignant mesothelioma, renal cell carcinoma, and atypical Spitz tumors; however, no other gene is known to be associated with increased risk for the combination of these cancers, as is seen in BAP1 tumor predisposition syndrome (BAP1-TPDS).

Table 2.

Disorders and Genes to Consider in the Differential Diagnosis BAP1-TPDS

Cancer Type/Associated DisorderGene(s)MOIComments and References
Uveal melanomaBRCA2ADIscovich et al [2002], Scott et al [2002], Sinilnikova et al [1999]
Malignant mesotheliomaUnknownUnknown
Cutaneous melanomaCDKN2A
CDK4
MC1R
MITF
ADPancreatic cancer is associated w/mutation of CDKN2A [Marzuka-Alcalá et al 2014]
Familial
clear cell
renal cell
carcinoma
Hereditary paraganglioma-pheochromocytoma syndromesSDHA
SDHB
SDHC
SDHD
SDHAF2
MAX
AD
Von Hippel-Lindau syndromeVHLAD
Translocation chromosome 3ADOMIM

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BAP1 tumor predisposition syndrome (BAP1-TPDS), the following evaluations are recommended [Rai et al 2016]:

  • Atypical Spitz (ATS) tumors, cutaneous melanoma (CM), and/or basal cell carcinoma (BCC). Full-body skin examination by a dermatologist with excision of any lesions suggestive of an atypical Spitz tumor
  • Uveal melanoma (UM). Dilated eye examination and imaging by an ocular oncologist
  • Malignant mesothelioma (MMe). No screening modalities exist; however, if an abdominal MRI is to be performed as recommended for ccRCC, consider evaluation of the peritoneum and pleura as well. Although some physicians recommend spiral chest CT for asymptomatic persons with a history of exposure to asbestos, others do not, given the possible increased risk of cancer from radiation exposure.
  • Clear cell renal cell carcinoma (ccRCC). Abdominal ultrasound examination, urinalysis, and abdominal MRI (consider also requesting assessment of the pleura and peritoneum)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The treatments for BAP1-TPDS tumors are those used in standard practice.

  • Uveal melanoma. Because of the increased aggressiveness of BAP1-related uveal melanoma, all uveal melanomas should be managed as the more aggressive tumors (ie., those determined to be class 2 by expression profiling and those with monosomy 3) [Njauw et al 2012].
  • Malignant mesothelioma. MMe is highly refractory to conventional therapies including aggressive surgical intervention and multimodality strategies; thus, a cure is unlikely.
  • Clear cell renal cell carcinoma is treated in the usual manner.

Prevention of Primary Manifestations

Uveal melanoma. Arc welding has been associated with risk of uveal melanoma and this should be avoided if possible.

Sunglasses with high UVA and UVB protection can reduce risk of cancer on the eyelids, but data regarding the benefit of sunglasses for uveal melanoma are lacking.

Malignant mesothelioma. As with all individuals, asbestos exposure and smoking should also be avoided.

Cutaneous melanoma. Primary prevention is limited to those measures typically used to reduce the risk for cutaneous melanoma, including limiting of sun exposure, regular use of sunscreen and protective clothing, and regular dermatologic examinations.

Surveillance

Consensus management recommendations have not been established; however, several groups have proposed variations of the following [Carbone et al 2012, Battaglia 2014, Rai et al 2016]:

  • Uveal melanoma. Yearly dilated eye examinations and imaging by an ocular oncologist beginning around age 11 years
  • Malignant mesothelioma. No reliable early disease symptoms or screening modalities
    Annual evaluation is recommended for late manifestations of mesothelioma, which can include chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, fever, upper body and face edema (chest mesothelioma) and abdominal pain, ascites, nausea, vomiting, and/or constipation (peritoneal mesothelioma). Annual physical examination is recommended to look for signs of pleurisy (pleural inflammation), peritonitis, ascites and/or pleural effusion.
    If an abdominal MRI is to be performed as recommended for ccRCC, consider evaluation of the peritoneum and pleura as well. Although some physicians recommend spiral chest CT for asymptomatic persons with a history of exposure to asbestos, others do not, given the possible increased risk of cancer from radiation exposure.
  • Cutaneous melanoma, basal cell carcinoma and atypical Spitz tumors. Annual full body dermatologic examinations beginning around age 20 years
  • Clear cell renal cell carcinoma. Protocol similar to von Hippel Lindau disease with annual abdominal ultrasound examination; consideration of annual urinalysis and abdominal MRI every two years

Agents/Circumstances to Avoid

Avoid the following:

  • Arc welding
  • Asbestos
  • Smoking
  • Unnecessary and prolonged sun exposure

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of screening and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Currently no open treatment trials specifically target patients with BAP1-TPDS.

One NCI-sponsored trial using vorinostat in the treatment of metastatic uveal melanoma is assessing BAP1 mutation status as a secondary outcome measure.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

BAP1 tumor predisposition syndrome (BAP1-TPDS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • To date, most individuals diagnosed with BAP1-TPDS have an affected parent. An affected parent may have BAP1-related tumors that differ from those of the proband.
  • Some individuals diagnosed with BAP1-TPDS may have the disorder as the result of a de novo germline BAP1 pathogenic variant. The proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo germline BAP1 pathogenic variant.
  • If the germline BAP1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported to date, it remains a possibility).
  • The family history of some individuals diagnosed with BAP1-TPDS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither of the parents has the germline BAP1 pathogenic variant identified in the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism (including the germline) for the variant and may never have developed a BAP1-related tumor; however, this has not been reported to date for BAP1-TPDS.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband has the BAP1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. However, penetrance appears to be incomplete (see Penetrance) and the types of BAP1-related tumors can vary among different members of the same family.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for BAP1-TPDS because of the possibility of reduced penetrance in a parent.
  • If the BAP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant. However, penetrance appears to be incomplete and the types of BAP1-related tumors can vary among different members of the same family.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the germline BAP1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the germline BAP1 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once a germline BAP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for BAP1-TPDS and preimplantation genetic diagnosis are possible options.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

BAP1 Tumor Predisposition Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
BAP13p21​.1Ubiquitin carboxyl-terminal hydrolase BAP1BAP1 @ LOVDBAP1BAP1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for BAP1 Tumor Predisposition Syndrome (View All in OMIM)

603089BRCA1-ASSOCIATED PROTEIN 1; BAP1
614327TUMOR PREDISPOSITION SYNDROME; TPDS

Molecular Genetic Pathogenesis

Although it has been been suggested that BAP1 functions as a tumor suppressor, this has not been completely established [Kadariya et al 2016]. It is a nuclear-localized deubiquitinating enzyme and acts as a chromatin-associated protein that is part of large multi-protein complexes which both positively and negatively regulate cellular proliferation [reviewed in Daou et al 2015]. It is recruited to promoter regions of genes involved in cellular proliferation to activate transcription and to promote repair at sites of DNA double strand breaks through homologous recombination [Daou et al 2015].

Gene structure. The BAP1 transcript NM_004656.3 has 3717 base pairs and 17 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Reported pathogenic (cancer-predisposing) variants include missense, nonsense, and splicing variants and small deletions and duplications (see Table A, HGMD).

One apparent BAP1 founder variant has been reported in four American families of German origin [Carbone et al 2015].

Normal gene product. The human BAP1 protein NP_004647.1 has 729 amino acids. Critical domains include: ubiquitin C-terminal hydrolase, BARD binding, HCF1 binding, ASXL1/2 binding, an ATM-dependent serine 592 phosphorylation site, and BRCA1 binding, as well as a nuclear localizing signal.

Abnormal gene product. BAP1-TPDS is caused by a cancer-predisposing variant in one BAP1 allele resulting in haploinsufficiency of the tumor suppressor protein BAP1. Tumors develop from certain cell types in which the second allele undergoes somatic mutation resulting in a complete absence of BAP1 tumor suppressor activity. Most atypical Spitz tumors (ASTs) analyzed by Wiesner et al [2012] showed loss of the remaining normal BAP1 allele by various somatic alterations and all showed loss of BAP1 protein in the nucleus.

Cancer and Benign Tumors

Sporadic tumors (including cholangiocarcinoma, mesothelioma, renal cell carcinoma and uveal melanoma) may occur as single tumors in the absence of any other findings of BAP1-TPDS and frequently harbor somatic variants in BAP1 that are not present in the germline [reviewed in Rai et al 2016]. In these circumstances predisposition to these tumors is not heritable.

References

Literature Cited

  • Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill J, Christopher B, Hovland P, Davidorf FH. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma and other cancers. J Med Genet. 2011;48:856–9. [PMC free article: PMC3825099] [PubMed: 21941004]
  • Aoude LG, Gartside M, Johansson P, Palmer JM, Symmons J, Martin NG, Montgomery GW, Hayward NK. Prevalence of germline BAP1, CDKN2A, and CDK4 mutations in an Australian population-based sample of cutaneous melanoma cases. Twin Res Hum Genet. 2015;18:126–33. [PubMed: 25787093]
  • Aoude LG, Vajdic CM, Kricker A, Armstrong B, Hayward NK. Prevalence of germline BAP1 mutation in a population-based sample of uveal melanoma cases. Pigment Cell Melanoma Res. 2013a;26:278–9. [PubMed: 23171164]
  • Aoude LG, Wadt K, Bojesen A, Crüger D, Borg A, Trent JM, Brown KM, Gerdes AM, Jönsson G, Hayward NK. A. BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers. PLoS One. 2013b;8:e72144. [PMC free article: PMC3747051] [PubMed: 23977234]
  • Battaglia A. The importance of multidisciplinary approach in early detection of BAP1 tumor predisposition syndrome: clinical management and risk assessment. Clin Med Insights Oncol. 2014;8:37–47. [PMC free article: PMC4011723] [PubMed: 24855403]
  • Baumann F, Flores E, Napolitano A, Kanodia S, Taioli E, Pass H, Yang H, Carbone M. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis. 2015;36:76–81. [PMC free article: PMC4291047] [PubMed: 25380601]
  • Betti M, Casalone E, Ferrante D, Romanelli A, Grosso F, Guarrera S, Righi L, Vatrano S, Pelosi G, Libener R, Mirabelli D, Boldorini R, Casadio C, Papotti M, Matullo G, Magnani C, Dianzani I. Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high-risk area. Genes Chrom Cancer. 2015;54:51–62. [PubMed: 25231345]
  • Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, Gaudino G, Powers A, Bryant-Greenwood P, Krausz T, Hyjek E, Tate R, Friedberg J, Weigel T, Pass HI, Yang H. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10:179. [PMC free article: PMC3493315] [PubMed: 22935333]
  • Carbone M, Flores EG, Emi M, Johnson TA, Tsunoda T, Behner D, Hoffman H, Hesdorffer M, Nasu M, Napolitano A, Powers A, Minaai M, Baumann F, Bryant-Greenwood P, Lauk O, Kirschner MB, Weder W, Opitz I, Pass HI, Gaudino G, Pastorino S, Yang H. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s. PLoS Genet. 2015;11:e1005633. [PMC free article: PMC4686043] [PubMed: 26683624]
  • Cheung M, Kadariya Y, Talarchek J, Pei J, Ohar JA, Kayaleh OR, Testa JR. Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction. Cancer Lett. 2015;369:261–5. [PMC free article: PMC4634709] [PubMed: 26409435]
  • Daou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Iannantuono NV, Nkwe NS, Motorina A, Pak H, Yu H, Wurtele H, Milot E, Mallette FA, Carbone M. Affar el B. The BAP1/ASXL2 histone H2A deubiquitinase complex regulates cell proliferation and is disrupted in cancer. J Biol Chem. 2015;290:28643–63. [PMC free article: PMC4661380] [PubMed: 26416890]
  • de la Fouchardière A, Cabaret O, Petre J, Aydin S, Leroy A, de Potter P, Pissaloux D, Haddad V, Bressac-de Paillerets B, Janin N. Primary leptomeningeal melanoma is part of the BAP1-related cancer syndrome. Acta Neuropathol. 2015b;129:921–3. [PubMed: 25900292]
  • de la Fouchardière A, Cabaret O, Savin L, Combemale P, Schvartz H, Penet C, Bonadona V, Soufir N, Bressac-de Paillerets B. Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet. 2015a;88:273–7. [PubMed: 25080371]
  • de Reyniès A, Jaurand MC, Renier A, Couchy G, Hysi I, Elarouci N, Galateau-Sallé F, Copin MC, Hofman P, Cazes A, Andujar P, Imbeaud S, Petel F, Pairon JC, Le Pimpec-Barthes F, Zucman-Rossi J, Jean D. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin Cancer Res. 2014;20:1323–34. [PubMed: 24443521]
  • Farley MN, Schmidt LS, Mester JL, Peña-Llopis S, Pavia-Jimenez A, Christie A, Vocke CD, Ricketts CJ, Peterson J, Middelton L, Kinch L, Grishin N, Merino MJ, Metwalli AR, Xing C, Xie XJ, Dahia PL, Eng C, Linehan WM, Brugarolas J. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res. 2013;11:1061–71. [PMC free article: PMC4211292] [PubMed: 23709298]
  • Gupta MP, Lane AM, DeAngelis MM, Mayne K, Crabtree M, Gragoudas ES, Kim IK. Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. JAMA Ophthalmol. 2015;133:881–7. [PubMed: 25974357]
  • Haas NB, Nathanson N. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21:81–90. [PMC free article: PMC3872053] [PubMed: 24359990]
  • Iscovich J, Abdulrazik M, Cour C, Fischbein A, Pe'er J, Goldgar DE. Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients. Int J Cancer. 2002;98:42–44. [PubMed: 11857383]
  • Kadariya Y, Cheung M, Xu J, Pei J, Sementino E, Menges CW, Cai KQ, Rauscher FJ, Klein-Szanto AJ, Testa JR. Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 2016;76:2836–44. [PMC free article: PMC4873414] [PubMed: 26896281]
  • Kalirai H, Dodson A, Faqir S, Damato BE, Coupland SE. Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing. Br J Cancer. 2014;111:1373–80. [PMC free article: PMC4183849] [PubMed: 25058347]
  • Kumar R, Taylor M, Miao B, Ji Z, Njauw JC, Jönsson G, Frederick DT, Tsao H. BAP1 has a survival role in cutaneous melanoma. J Invest Dermatol. 2015;135:1089–97. [PMC free article: PMC4366338] [PubMed: 25521456]
  • Marzuka-Alcalá A, Gabree MJ, Tsao H. Melanoma Susceptibility Genes and Risk Assessment. Methods Mol Biol. 2014;1102:381–93. [PubMed: 24258989]
  • McDonnell KJ, Gallanis GT, Heller KA, Melas M, Idos GI, Culver JO, Martin S-E, Peng DH, Gruber SB. A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer. Cancer Genet. 2016;209:75–81. [PubMed: 26774355]
  • Mochel MC, Piris A, Nose V, Hoang MP. Loss of BAP1 expression in basal cell carcinomas in patients with germline BAP1 mutations. Am J Clin Pathol. 2015;143:901–4. [PubMed: 25972334]
  • Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, DeAngelis MM, Gragoudas E, Duncan LM, Tsao H. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 2012;7:e35295. [PMC free article: PMC3335872] [PubMed: 22545102]
  • Ohar JA, Cheung M, Talarchek J, Howard SE, Howard TD, Hesdorffer M, Peng H, Rauscher FJ, Testa JR. Germline BAP1 mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer. Cancer Res. 2016;76:206–15. [PMC free article: PMC4715907] [PubMed: 26719535]
  • Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44:751–9. [PMC free article: PMC3788680] [PubMed: 22683710]
  • Pilarski R, Cebulla CM, Massengill JB, Rai K, Rich T, Strong L, McGillivray B, Asrat M-J, Carbon M, Davidorf FH, Abdel-Rahman MH. Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome. Genes Chromosomes Cancer. 2014;53:177–82. [PMC free article: PMC4041196] [PubMed: 24243779]
  • Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manié E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, Stern MH. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 2013;92:974–80. [PMC free article: PMC3675229] [PubMed: 23684012]
  • Rai K, Pilarski R, Cebulla CM, Abdel-Rahman MH. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 2016;89:285–94. [PMC free article: PMC4688243] [PubMed: 26096145]
  • Rusch VW, Rimner A, Krug LM. The challenge of malignant pleural mesothelioma: new directions. J Thorac Oncol. 2014;9:271–2. [PubMed: 24518084]
  • Scott RJ, Vajdic CM, Armstrong BK, Ainsworth CJ, Meldrum CJ, Aitken JF, Kricker A. BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer. 2002;102:188–91. [PubMed: 12385017]
  • Singhi AD, Krasinskas AM, Choudry HA, Bartlett DL, Pingpank JF, Zeh HJ, Luvison A, Fuhrer K, Bahary N, Seethala RR, Dacic S. The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. Mod Pathol. 2016;29:14–24. [PubMed: 26493618]
  • Sinilnikova OM, Egan KM, Quinn JL, Boutrand L, Lenoir GM, Stoppa-Lyonnet D, Desjardins L, Levy C, Goldgar D, Gragoudas ES. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999;82:325–8. [PubMed: 10399947]
  • Sneddon S, Leon JS, Dick IM, Cadby G, Olsen N, Brims F, Allcock RJN, Moses EK, Melton PE, de Klerk N, Musk AW, Robinson BWS, Creaney J. Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma. Gene. 2015;563:103–5. [PubMed: 25796603]
  • Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43:1022–5. [PMC free article: PMC3184199] [PubMed: 21874000]
  • Turunen JA, Markkinen S, Wilska R, Saarinen S, Raivio V, Täll M, Lehesjoki AE, Kivelä TT. BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma. Ophthalmology. 2016;123:1112–7. [PubMed: 26876698]
  • Wadt K, Choi J, Chung JY, Kiilgaard J, Heegaard S, Drzewiecki KT, Trent JM, Hewitt SM, Hayward NK, Gerdes AM, Brown KM. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res. 2012;25:815–8. [PubMed: 22889334]
  • Wadt KA, Aoude LG, Johansson P, Solinas A, Pritchard A, Crainic O, Andersen MT, Kiilgaard JF, Heegaard S, Sunde L, Federspiel B, Madore J, Thompson JF, McCarthy SW, Goodwin A, Tsao H, Jönsson G, Busam K, Gupta R, Trent JM, Gerdes AM, Brown KM, Scolyer RA, Hayward NK. A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin Genet. 2015;88:267–72. [PubMed: 25225168]
  • Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H, Bastian BC. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36:818–30. [PMC free article: PMC3354018] [PubMed: 22367297]
  • Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rütten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–21. [PMC free article: PMC3328403] [PubMed: 21874003]
  • Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, Sementino E, Tan Y, Menges CW, Cai KQ, Litwin S, Peng H, Karar J, Rauscher FJ, Testa JR. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74:4388–97. [PMC free article: PMC4165574] [PubMed: 24928783]

Chapter Notes

Author Notes

Author’s website

Our group’s research is focused on identifying and characterizing hereditary causes of uveal melanoma. We were one of three groups co-reporting on the identification of the BAP1 tumor predisposition syndrome. We offer research analysis of BAP1 in families with histories suggestive of BAP1-TPDS and are performing exome and other analyses on high-risk UM families without identifiable genetic causes. To discuss enrolling a patient please contact ude.cmuso@iksralip.trebor.

Revision History

  • 13 October 2016 (bp) Review posted live
  • 3 May 2016 (rp) Original submission
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK390611PMID: 27748099

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...