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; 1993-2021.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

BAP1 Tumor Predisposition Syndrome

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

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

Author Information

Initial Posting: ; Last Update: September 17, 2020.

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC). Hepatocellular carcinoma, cholangiocarcinoma, and meningioma may also be associated with BAP1-TPDS. 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 occurring in the general population. Due to the limited number of families reported to date, the penetrance, natural history, and frequencies of BAP1-associated tumors are yet to be determined. Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, neuroendocrine carcinoma, non-small-cell lung adenocarcinoma, thyroid cancer, and urinary bladder cancer.

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: Treatment of CM and BCC per established clinical guidelines. UM: because of the increased aggressiveness of BAP1-related UM, management should be the same as the more aggressive class 2 or monosomy 3 tumors. MMe treatment per oncologist familiar with BAP1-MMe; RCC treatment per established management guidelines.

Prevention of primary manifestations: UM: avoid arc-welding. MMe: avoid asbestos exposure (including naturally occurring tremolite and erionite) and smoking. CM and BCC: limit sun exposure, use sunscreen and protective clothing, and have regular dermatologic examinations.

Surveillance: BIMT, CM, BCC: annual full-body dermatologic examinations beginning around age 18 years. Baseline whole-body imaging in those with a large number of lesions; repeat as needed. Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. UM: yearly dilated eye examinations and at least baseline fundus imaging beginning around age 11 years. Refer any pigmented intraocular lesion to an ocular oncologist for follow up and management. MMe: no screening modalities exist; however, annual physical examination is recommended. If an abdominal MRI is to be performed as recommended for RCC, consider evaluation of the peritoneum and pleura as well. While 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. RCC: annual clinical examination; abdominal ultrasound every two years alternating with MRI every two years starting at age 30 years.

Agents/circumstances to avoid: Arc welding, asbestos including naturally occurring tremolite and erionite, smoking, unnecessary and prolonged sun exposure, routine chest x-ray and CT examinations.

Evaluation of relatives at risk: Clarify the genetic status of 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 and preimplantation genetic testing are possible.

Diagnosis

No diagnostic criteria have been published for the BAP1 tumor predisposition syndrome (BAP1-TPDS). In one review, 90% of families reported with a germline BAP1 pathogenic variant met the criteria outlined in Suggestive Findings [Rai et al 2016].

Suggestive Findings

BAP1-TPDS should be suspected in an individual who has EITHER of the following:

  • Two or more confirmed BAP1-TPDS tumors*
  • 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):

  • BAP1-inactivated melanocytic tumors (BIMT). Formerly called atypical Spitz tumors, these may be the most common manifestation of BAP1-TPDS, and may result in the initial identification of a proband. BIMT 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; in addition, BIMT usually have somatic BRAF pathogenic variant p.Val600Glu.
  • Uveal (eye) melanoma (UM)
  • Malignant mesothelioma (MMe)
  • Cutaneous melanoma (CM)
  • Renal cell carcinoma (RCC)
  • Basal cell carcinoma (BCC)
  • Hepatocellular carcinoma, cholangiocarcinoma, and meningioma. These now appear to be less common manifestations of BAP1-TPDS.

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

  • Breast cancer
  • Neuroendocrine tumors
  • Non-small-cell lung adenocarcinoma
  • Thyroid cancer
  • Urinary bladder 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 multigene panel:

  • Single-gene testing. Sequence analysis of BAP1 is performed. The identification of partial and whole-gene deletions in a subset of individuals supports the benefit of doing gene-targeted deletion/duplication analysis concurrently, or if no BAP1 pathogenic variant is found on sequence analysis.
  • A multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in BAP1 Tumor Predisposition Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
BAP1Sequence analysis 3>87.5% 4
Gene-targeted deletion/duplication analysis 5<12.5% 6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.

Clinical Characteristics

Clinical Description

BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with increased risk for a number of cancers and a specific skin lesion, BAP1-inactivated melanocytic tumor (BIMT; formerly called atypical Spitz tumor). Affected individuals can have more than one type of primary cancer [Abdel-Rahman et al 2011, Testa et al 2011, Wiesner et al 2011, Popova et al 2013, Walpole et al 2018].

Because of the limited number of families reported to date and ascertainment bias of 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. In an attempt to adjust for ascertainment bias, Walpole et al [2018] (as noted below) compared the prevalence of each component tumor in probands with BAP1-TPDS to the prevalence in relatives known to also have a BAP1 pathogenic variant. It has been well established, however, that the following tumor types are associated with BAP1-TPDS.

BAP1-inactivated melanocytic tumor (BIMT; formerly called atypical Spitz tumor). The natural history of these lesions is not clearly known. It appears that individuals with BAP1-TPDS typically have multiple lesions [Haugh et al 2017]. BIMT 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; in addition, BIMT usually have somatic BRAF pathogenic variant p.Val600Glu.

Uveal melanoma (UM) is the cancer most commonly reported in persons with BAP1-TPDS (36% of probands and 16% of relatives reported with BAP1-TPDS have UM), and it is the cancer with the earliest reported age of diagnosis (age 16 years) [Walpole et al 2018]. Median age of onset of UM in persons with BAP1-TPDS is 53 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 reduced survival [Njauw et al 2012, Rai et al 2016]. In one study, mean length of survival in persons whose UM 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 (25% of probands and 19% of relatives) identified in individuals with BAP1-TPDS [Walpole et al 2018]. Several studies have shown that the median age of onset of MMe in individuals with BAP1-TPDS was significantly earlier (55 to 58 years) than that of sporadic MMe (68-72 years) [Baumann et al 2015, Ohar et al 2016, Walpole et al 2018]. In the general population, 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, Walpole et al 2018]. 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 [Walpole et al 2018].

In contrast to survival in persons with BAP1-related cutaneous melanoma, UM, or renal cell carcinoma, survival in persons with BAP1-related MMe may be significantly longer, especially in those with pleural mesothelioma [Baumann et al 2015, Pastorino et al 2018, Wang et al 2018, Hassan et al 2019].

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]. Interestingly, Walpole et al [2018] found CM in 45% of probands but in no relatives affected with BAP1-TPDS [Walpole et al 2018]. Multiple primary cutaneous melanomas are common. The median age of onset of CM in individuals with BAP1-TPDS is earlier than in the general population (39 vs 58 years). While it is possible that BAP1-related CM is more aggressive than CM in the general population, the data are currently inconsistent [Gupta et al 2015, Kumar et al 2015, Rai et al 2016, Liu-Smith & Lu 2020].

Renal cell carcinoma (RCC). Heterozygous BAP1 germline pathogenic variants are specifically associated with an increased risk for RCC, in particular those with clear cell morphology [Haas & Nathanson 2014]. Walpole et al [2018] found RCC in 10% of probands and relatives with BAP1-TPDS, although the specific histology was not always known and additional morphologies including papillary and chromophobe cell tumors were also observed. Median age of RCC diagnosis appears to be younger in persons with BAP1-TPDS than in the general population (47-50 vs 64 years), and length of survival is decreased in persons with BAP1-related RCC [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 somatic PBRM1 pathogenic variants (which are common in RCC not associated with pathogenic variants in BAP1) [Peña-Llopis et al 2012].

Basal cell carcinoma (BCC) has recently been confirmed as a tumor in the BAP1-TPDS spectrum [de la Fouchardière et al 2015b, Mochel et al 2015, Wadt et al 2015]. Multiple primary basal cell carcinomas are common. Walpole et al [2018] found that the median age of diagnosis for non-melanoma skin cancer (primarily BCC) was 44 years.

Meningioma, particularly a high-grade rhabdoid subtype, has been suggested to be associated with BAP1-TPDS [Abdel-Rahman et al 2011, Cheung et al 2015, de la Fouchardière et al 2015a, Wadt et al 2015, Shankar et al 2017]. This is further supported by identification of this tumor in 8.5% of probands with BAP1-TPDS and 2.2% of relatives with the BAP1 pathogenic variant.

Cholangiocarcinoma has also been suggested to be part of BAP1-TPDS [Njauw et al 2012, Pilarski et al 2014, Wadt et al 2015]. Walpole et al [2018] found this cancer in 1.4% of probands with BAP1-TPDS but in none of the relatives.

Hepatocellular carcinoma (HCC). Germline BAP1 pathogenic variants have been observed in 0.5% of unselected individuals with HCC [Huang et al 2018]. Walpole et al [2018] identified HCC in 0.7% of probands with BAP1-TPDS and 1.6% of relatives with the BAP1 pathogenic variant.

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 for BAP1-TPDS have been published.

Most families (104 of 141) have had a unique BAP1 pathogenic variant; a number of recurrent pathogenic variants have been reported [Walpole et al 2018] (see Molecular Genetics).

Penetrance

The penetrance of the BAP1-TPDS appears to be high based on the published literature, with 88% of probands and 82.5% of relatives with a heterozygous germline BAP1 pathogenic variant having 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. Also, the majority of the study participants were ascertained based on their strong family history of cancer. Given these biases, an accurate estimate of penetrance cannot be determined at this time. In attempting to adjust for this, Walpole et al [2018] found a significantly lower prevalence of BAP1-related tumors in affected relatives compared to probands (see Prevalence).

Nomenclature

BAP1-inactivated melanocytic tumors have also been called the following:

  • Atypical Spitz tumors
  • 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. Based on data from the Genome Aggregation Database (gnomAD), the carrier frequency is 1:26,837 in the general population. In the cancer cohort from the TCGA, the frequency was 8:10,389 (1:1,299).

The prevalence of BAP1-TPDS ranges from 1%-2% in persons with UM,1%-3% in persons with MMe [Huang et al 2018, Panou et al 2018], 1%-1.5% in those with RCC [Carlo et al 2018, Wu et al 2019], and 0.5% in persons with HCC. Several large studies showed that BAP1-TPDS is rare in those with CM (0.1%) [Aoude et al 2015, O'Shea et al 2017]. The prevalence of BAP1-TPDS in persons with other cancers is unknown.

UM. The prevalence of germline BAP1 pathogenic variants in unselected individuals with UM is 1%-2% [Aoude et al 2013a, Gupta et al 2015, Repo et al 2019]; in contrast, the frequency is 20%-30% in persons with UM who have a family history of UM [Turunen et al 2016, Rai et al 2017].

MMe. Germline BAP1 pathogenic variants have been identified in 1%-3% of simplex cases and 6%-7.7% (9:153) of individuals with familial MMe [Betti et al 2015, Ohar et al 2016, Betti et al 2018].

CM. Germline BAP1 pathogenic variants were observed rarely in two large studies of sporadic CM with a prevalence of 3:1,197 (0.25%) and 0:1109 [Aoude et al 2015, O'Shea et al 2017]. Also, germline BAP1 pathogenic variants are rare in familial CM (0%-0.7%), particularly in those with no other cancers observed in the family [Njauw et al 2012, Boru et al 2019, Potjer et al 2019].

Differential Diagnosis

Pathogenic variants in genes other than BAP1 can be associated with uveal melanoma, cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma; 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.

Genes to Consider in the Differential Diagnosis BAP1 Tumor Predisposition Syndrome

Cancer TypeGene / Genetic
Mechanism
Comments/References
Uveal melanomaBRCA1
BRCA2
MBD4
PALB2
Sinilnikova et al [1999], Iscovich et al [2002], Scott et al [2002], Moran et al [2012], Abdel-Rahman et al [2020a], Abdel-Rahman et al [2020b]
Malignant mesotheliomaCDKN2A 1Panou et al [2018]
Cutaneous melanomaCDKN2A
CDK4
MC1R
MITF
Pancreatic cancer is assoc w/CDKN2A pathogenic variants [Marzuka-Alcalá et al 2014].
Hereditary renal cell carcinomaVHLSee Von Hippel-Lindau Syndrome.
Xp11
translocation
Xp11 translocation renal cell carcinoma (OMIM 300854)
FHHereditary cutaneous leiomyomatosis, renal cell cancer, uterine leiomyomas (fibroids); see FH Tumor Predisposition Syndrome.
FLCN
  • Renal tumors: hybrid oncocytic, chromophobe, oncocytoma, papillary, clear cell renal cell carcinoma
  • Cutaneous: fibrofolliculomas/trichodiscomas
  • Pulmonary: lung cysts, spontaneous pneumothoraces; see Birt-Hogg-Dubé Syndrome.
METHereditary papillary renal cell carcinoma (OMIM 605074)

Monogenic disorders included in this table are inherited in an autosomal dominant manner.

1.

Panou et al [2018] describe several additional genes; however, only BAP1 and CDKN2A remain significant if the Bonferroni correction is applied.

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 evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended in a multidisciplinary team approach [Rai et al 2016, Star et al 2018].

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with BAP1 Tumor Predisposition Syndrome

System/
Concern
EvaluationComment
BIMT, CM,
&/or BCC
  • Full-body skin exam by dermatologist specializing in melanoma
  • Consider whole-body imaging if large number of lesions.
  • Excision of lesions suggestive of BIMT is debated.
  • Mgmt of other suspicious melanocytic lesions & BCC per established clinical guidelines
Beginning at age ~18 yrs
UM
  • Dilated eye exam & baseline dilated fundus imaging
  • Refer any suspected lesion to ophthalmologist specializing in mgmt of UM (ocular oncologist) for proper diagnosis & mgmt.
Beginning at age ~11 yrs
MMe
  • No consensus on screening modalities exists.
  • Abdominal & respiratory clinical exam w/investigation of any suspected symptoms
  • Asymptomatic imaging surveillance w/US (renal/abdominal & chest) or MRI (abdominal & chest w/diffusion-weighted sequences)
  • Beginning at age 30 yrs
  • Combined w/RCC eval
RCCAbdominal exam & investigation of any suspected symptoms
  • Beginning at age 30 yrs
  • Combined w/MMe eval
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of BAP1-TPDS to facilitate medical & personal decision making

BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; MOI = mode of inheritance; UM = uveal melanoma

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

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

Table 4.

Treatment of Manifestations in Individuals with BAP1 Tumor Predisposition Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
BIMT, CM, &/or BCC
  • Annual dermatologic exam & whole-body imaging recommended for stable asymptomatic BIMT lesions
  • Treatment of CM & BCC per established clinical guidelines
Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions [Star et al 2018].
UMManage UMs as more aggressive tumors (i.e., those determined to be Class 2 by expression profiling & those w/monosomy 3)Because of ↑ aggressiveness of BAP1-related UM [Njauw et al 2012]
MMeTreatment per oncologist familiar with BAP1-MMe
  • MMe is highly refractory to conventional therapies incl aggressive surgical intervention & multimodality strategies; thus, a cure is unlikely.
  • Recent studies suggest that BAP1-related MMe could respond better to chemotherapy.
  • Several clinical trials incl w/PARP inhibitor are ongoing.
RCCTreatment per established management guidelinesSeveral clinical trials incl w/PARP inhibitor are ongoing.

BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; PARP = poly ADP ribose polymerase; UM = uveal melanoma

Prevention of Primary Manifestations

Uveal melanoma (UM). Arc welding has been associated with risk of UM 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 UM are lacking.

Malignant mesothelioma. As with all individuals, asbestos exposure (including naturally occurring tremolite and erionite) and smoking should be avoided.

Cutaneous melanoma (CM). Primary prevention is limited to those measures typically used to reduce the risk for CM, 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 (see Table 5) [Carbone et al 2012, Battaglia 2014, Rai et al 2016, Star et al 2018].

Table 5.

Recommended Surveillance for Individuals with BAP1 Tumor Predisposition Syndrome

System/ConcernEvaluationFrequency
BIMT, CM,
&/or BCC
  • Full-body skin exam by dermatologist specializing in melanoma
  • Consider whole-body imaging if large number of lesions.
  • Excision of lesions suggestive of BIMT is debated.
  • Mgmt of other suspicious melanocytic lesions & BCC per established clinical guidelines
Annually beginning at age ~18 yrs
UM
  • Dilated eye exam & baseline dilated fundus imaging preferably by ophthalmologist trained in diagnosis & mgmt of UM (ocular oncologist)
  • Alternatively, follow up by ophthalmologist w/referral of suspected lesions to ocular oncologist for proper diagnosis & management
Annually beginning at age ~11 yrs
MMe (pleural
& peritoneal)
  • No consensus on screening modalities exists.
  • Clinical eval for signs/symptoms of pleurisy (pleural inflammation), peritonitis, ascites, &/or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, fever, upper body & face edema, abdominal pain, nausea, vomiting, &/or constipation
  • If abdominal MRI is to be performed as recommended for RCC, consider eval of peritoneum & pleura as well.
  • Some physicians recommend spiral chest CT for asymptomatic persons w/history of exposure to asbestos; others do not, given possible ↑ risk of cancer from radiation exposure.
  • Avoid routine surveillance w/chest x-ray or CT exam.
RCC
  • Annual clinical exam w/investigation of any suspected symptoms such as abdominal pain &/or hematuria
  • Asymptomatic imaging surveillance using US (renal/abdominal & chest) & MRI (abdominal & chest w/diffusion-weighted sequences)
  • Beginning at age 30 yrs
  • MRI every 2 yrs
  • US every 2 yrs (alternating w/MRIs)

BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; UM = uveal melanoma

Agents/Circumstances to Avoid

Avoid the following:

  • Arc welding
  • Asbestos
  • Smoking
  • Unnecessary and prolonged sun exposure
  • Routine chest x-ray and CT examinations

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the BAP1 pathogenic variant in the family. Family members who have a BAP1 pathogenic variant should be offered regular lifelong surveillance. Family members who have not inherited the pathogenic variant and their subsequent offspring have risks similar to the general population.

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 individuals with BAP1-TPDS, but several trials are currently open for individuals with somatic BAP1 pathogenic variants, including PARP inhibitor therapies as single or combination therapies.

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 in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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. To date, a de novo pathogenic variant has been reported in one individual (both parents tested negative for the variant identified in the proband) [Walpole et al 2018].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo germline pathogenic variant (i.e., a proband who appears to be the only affected family member).
  • If the germline BAP1 pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental leukocyte DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. (No instances of parental germline mosaicism for a BAP1 pathogenic variant have been reported to date.)
  • 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.

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 identified in the proband, 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.
  • If the BAP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the BAP1 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for BAP1-TPDS because of the possibility of reduced penetrance in a heterozygous parent or the theoretic 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 genetic 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 family members requires prior identification of the germline BAP1 pathogenic variant in the family.

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 – Health Professional Version (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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)
    250 Williams Street Northwest
    Atlanta GA 30303
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    22nd Floor
    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 Pathogenesis

BAP1 encodes BAP1, a ubiquitin carboxyl-terminal hydrolase. BAP1 is a nuclear-localized deubiquitinating enzyme and acts as a chromatin-associated protein that is part of large multiprotein complexes that 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]. BAP1 cytoplasmic function is thought to be important in apoptosis [Bononi et al 2017].

Mechanism of disease causation. Loss of function. A pathogenic variant in one BAP1 allele results in haploinsufficiency of BAP1, a tumor suppressor protein. Tumors develop when the second allele acquires a second pathogenic variant resulting in complete loss of BAP1 tumor suppressor activity. Most BAP1-inactivated melanocytic tumors 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.

Table 6.

Notable BAP1 Pathogenic Variants

Reference SequencesDNA Nucleotide
Change
Predicted Protein
Change
Comment [Reference]
NM_004656​.4
NP_004647​.1
c.1717delCp.Leu573TrpfsTer3Founder variant identified in several families from United States w/common ancestor [Carbone et al 2015, Walpole et al 2018, Boru et al 2019]
c.1780_1781insTp.Gly594ValfsTer49Founder variant in Finland
c.178C>Tp.Arg60TerObserved in multiple subjects from different populations; proven through haplotype studies to have arisen independently multiple times [Walpole et al 2018]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Cancer and Benign Tumors

Sporadic tumors (including cholangiocarcinoma, hepatocellular carcinoma, 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.

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 BAP1 tumor predisposition syndrome (BAP1-TPDS). 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.

Author History

Mohamed Abdel-Rahman, MD, PhD (2016-present)
Maria Carlo, MD (2020-present)
Colleen Cebulla, MD, PhD (2016-present)
Robert Pilarski, MS, LGC, MSW (2016-present)
Karan Rai, BS; The Ohio State University (2016-2020)

Revision History

  • 17 September 2020 (sw) Comprehensive update posted live
  • 9 April 2020 (rp) Revision: clarification of starting age for screening
  • 13 October 2016 (bp) Review posted live
  • 3 May 2016 (rp) Original submission

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]
  • Abdel-Rahman MH, Pilarski R, Fatehchand K, Davidorf FH, Cebulla CM. Hereditary predisposition to uveal melanoma. In: Gao XR, ed. Genetics and Genomics of Eye Disease: Advancing to Precision Medicine. Cambridge, MA: Academic Press; 2020a:137-51.
  • Abdel-Rahman MH, Rai K, Pilarski R, Davidorf FH, Cebulla CM. Germline BAP1 mutations misreported as somatic based on tumor-only testing. Fam Cancer. 2016;15:327–30. [PMC free article: PMC4983194] [PubMed: 26748926]
  • Abdel-Rahman MH, Sample KM, Pilarski R, Walsh T, Grosel T, Kinnamon D, Boru G, Massengill JB, Schoenfield L, Kelly B, Gordon D, Johansson P, DeBenedictis MJ, Singh A, Casadei S, Davidorf FH, White P, Stacey AW, Scarth J, Fewings E, Tischkowitz M, King MC, Hayward NK, Cebulla CM. Whole exome sequencing identifies candidate genes associated with hereditary predisposition to uveal melanoma. Ophthalmology. 2020b;127:668–78. [PMC free article: PMC7183432] [PubMed: 32081490]
  • 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, Aspesi A, Ferrante D, Sculco M, Righi L, Mirabelli D, Napoli F, Rondón-Lagos M, Casalone E, Vignolo Lutati F, Ogliara P, Bironzo P, Gironi CL, Savoia P, Maffè A, Ungari S, Grosso F, Libener R, Boldorini R, Valiante M, Pasini B, Matullo G, Scagliotti G, Magnani C, Dianzani I. Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes. Genes Chromosomes Cancer. 2018;57:573–83. [PubMed: 30338612]
  • 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]
  • Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, Pellegrini L, Signorato V, Olivetto F, Pastorino S, Nasu M, Napolitano A, Gaudino G, Morris P, Sakamoto G, Ferris LK, Danese A, Raimondi A, Tacchetti C, Kuchay S, Pass HI, Affar EB, Yang H, Pinton P, Carbone M. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature. 2017;546:549–53. [PMC free article: PMC5581194] [PubMed: 28614305]
  • Boru G, Grosel TW, Pilarski R, Stautberg M, Massengill JB, Jeter J, Singh A, Marino MJ, McElroy JP, Davidorf FH, Cebulla CM, Abdel-Rahman MH. Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer. Genes Chromosomes Cancer. 2019;58:650–6. [PMC free article: PMC6612571] [PubMed: 30883995]
  • 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]
  • Carlo MI, Mukherjee S, Mandelker D, Vijai J, Kemel Y, Zhang L, Knezevic A, Patil S, Ceyhan-Birsoy O, Huang KC, Redzematovic A, Coskey DT, Stewart C, Pradhan N, Arnold AG, Hakimi AA, Chen YB, Coleman JA, Hyman DM, Ladanyi M, Cadoo KA, Walsh MF, Stadler ZK, Lee CH, Feldman DR, Voss MH, Robson M, Motzer RJ, Offit K. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4:1228–35. [PMC free article: PMC6584283] [PubMed: 29978187]
  • 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. 2015a;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. 2015b;88:273–7. [PubMed: 25080371]
  • 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]
  • Hassan R, Morrow B, Thomas A, Walsh T, Lee MK, Gulsuner S, Gadiraju M, Panou V, Gao S, Mian I, Khan J, Raffeld M, Patel S, Xi L, Wei JS, Hesdorffer M, Zhang J, Calzone K, Desai A, Padiernos E, Alewine C, Schrump DS, Steinberg SM, Kindler HL, King MC, Churpek JE. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proc Natl Acad Sci U S A. 2019;116:9008–13. [PMC free article: PMC6500142] [PubMed: 30975761]
  • Haugh AM, Njauw CN, Bubley JA, Verzì AE, Zhang B, Kudalkar E, VandenBoom T, Walton K, Swick BL, Kumar R, Rana HQ, Cochrane S, McCormick SR, Shea CR, Tsao H, Gerami P. Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature. JAMA Dermatol. 2017;153:999–1006. [PMC free article: PMC5710339] [PubMed: 28793149]
  • Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, Hucthagowder V, Kim TB, Hahn A, Wang C, McLellan MD, Al-Mulla F, Johnson KJ. Cancer Genome Atlas Research Network, Lichtarge O, Boutros PC, Raphael B, Lazar AJ, Zhang W, Wendl MC, Govindan R, Jain S, Wheeler D, Kulkarni S, Dipersio JF, Reimand J, Meric-Bernstam F, Chen K, Shmulevich I, Plon SE, Chen F, Ding L. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173:355–70.e14. [PMC free article: PMC5949147] [PubMed: 29625052]
  • 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]
  • Liu-Smith F, Lu Y. Opposite roles of BAP1 in overall survival of uveal melanoma and cutaneous melanoma. J Clin Med. 2020;9:411. [PMC free article: PMC7074098] [PubMed: 32028647]
  • 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. [PMC free article: PMC6447287] [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]
  • Moran A, O'Hara C, Khan S, Shack L, Woodward E, Maher ER, Lalloo F, Evans DG. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer. 2012;11:235–42. [PubMed: 22187320]
  • 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]
  • O'Shea SJ, Robles-Espinoza CD, McLellan L, Harrigan J, Jacq X, Hewinson J, Iyer V, Merchant W, Elliott F, Harland M, Bishop DT, Newton-Bishop JA, Adams DJ. A population-based analysis of germline BAP1 mutations in melanoma. Hum Mol Genet. 2017;26:717–28. [PMC free article: PMC5409081] [PubMed: 28062663]
  • Panou V, Gadiraju M, Wolin A, Weipert CM, Skarda E, Husain AN, Patel JD, Rose B, Zhang SR, Weatherly M, Nelakuditi V, Knight Johnson A, Helgeson M, Fischer D, Desai A, Sulai N, Ritterhouse L, Røe OD, Turaga KK, Huo D, Segal J, Kadri S, Li Z, Kindler HL, Churpek JE. Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. J Clin Oncol. 2018;36:2863–71. [PMC free article: PMC6804864] [PubMed: 30113886]
  • Pastorino S, Yoshikawa Y, Pass HI, Emi M, Nasu M, Pagano I, Takinishi Y, Yamamoto R, Minaai M, Hashimoto-Tamaoki T, Ohmuraya M, Goto K, Goparaju C, Sarin KY, Tanji M, Bononi A, Napolitano A, Gaudino G, Hesdorffer M, Yang H, Carbone M. A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations. J Clin Oncol. 2018;36:JCO2018790352. [PMC free article: PMC7162737] [PubMed: 30376426]
  • 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]
  • Potjer TP, Bollen S, Grimbergen AJEM, van Doorn R, Gruis NA, van Asperen CJ, Hes FJ, van der Stoep N, et al. Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families. Int J Cancer. 2019;144:2453–64. [PMC free article: PMC6590189] [PubMed: 30414346]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rai K, Pilarski R, Boru G, Rehman M, Saqr AH, Massengill JB, Singh A, Marino MJ, Davidorf FH, Cebulla CM. H Abdel-Rahman M. Germline BAP1 alterations in familial uveal melanoma. Genes Chromosomes Cancer. 2017;56:168–74. [PMC free article: PMC5490375] [PubMed: 27718540]
  • 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]
  • Repo P, Järvinen RS, Jäntti JE, Markkinen S, Täll M, Raivio V, Turunen JA, Kivelä TT. Population-based analysis of BAP1 germline variations in patients with uveal melanoma. Hum Mol Genet. 2019;28:2415–26. [PubMed: 31058963]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • 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]
  • Shankar GM, Abedalthagafi M, Vaubel RA, Merrill PH, Nayyar N, Gill CM, Brewster R, Bi WL, Agarwalla PK, Thorner AR, Reardon DA, Al-Mefty O, Wen PY, Alexander BM, van Hummelen P, Batchelor TT, Ligon KL, Ligon AH, Meyerson M, Dunn IF, Beroukhim R, Louis DN, Perry A, Carter SL, Giannini C, Curry WT Jr, Cahill DP, Barker FG 2nd, Brastianos PK, Santagata S. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol. 2017;19:535–45. [PMC free article: PMC5464371] [PubMed: 28170043]
  • 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]
  • Star P, Goodwin A, Kapoor R, Conway RM, Long GV, Scolyer RA, Guitera P. Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy. Eur J Cancer. 2018;92:48–53. [PubMed: 29413689]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Tesch ME, Pater JA, Vandekerkhove G, Wang G, Binnington K, So AI, Wyatt AW, Eigl BJ. Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer. NPJ Genom Med. 2020;5:12. [PMC free article: PMC7089973] [PubMed: 32218990]
  • 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. [PMC free article: PMC7453745] [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]
  • Walpole S, Pritchard AL, Cebulla CM, Pilarski R, Stautberg M, Davidorf FH, de la Fouchardière A, Cabaret O, Golmard L, Stoppa-Lyonnet D, Garfield E, Njauw CN, Cheung M, Turunen JA, Repo P, Järvinen RS, van Doorn R, Jager MJ, Luyten GPM, Marinkovic M, Chau C, Potrony M, Höiom V, Helgadottir H, Pastorino L, Bruno W, Andreotti V, Dalmasso B, Ciccarese G, Queirolo P, Mastracci L, Wadt K, Kiilgaard JF, Speicher MR, van Poppelen N, Kilic E, Al-Jamal RT, Dianzani I, Betti M, Bergmann C, Santagata S, Dahiya S, Taibjee S, Burke J, Poplawski N, O'Shea SJ, Newton-Bishop J, Adlard J, Adams DJ, Lane AM, Kim I, Klebe S, Racher H, Harbour JW, Nickerson ML, Murali R, Palmer JM, Howlie M, Symmons J, Hamilton H, Warrier S, Glasson W, Johansson P, Robles-Espinoza CD, Ossio R, de Klein A, Puig S, Ghiorzo P, Nielsen M, Kivelä TT, Tsao H, Testa JR, Gerami P, Stern MH, Paillerets BB, Abdel-Rahman MH, Hayward NK. Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J Natl Cancer Inst. 2018;110:1328–41. [PMC free article: PMC6292796] [PubMed: 30517737]
  • Wang Z, Wang XY, Li J, Zhu WW. Prognostic and clinicopathological significance of BAP1 protein expression in different types of cancer-a meta-analysis. Genet Test Mol Biomarkers. 2018;22:115–26. [PubMed: 29266978]
  • 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]
  • Wu J, Wang H, Ricketts CJ, Yang Y, Merino MJ, Zhang H, Shi G, Gan H, Linehan WM, Zhu Y, Ye D. Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease. Cancer. 2019;125:1060–9. [PubMed: 30548481]
  • 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]
Copyright © 1993-2021, 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 (© 1993-2021 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
  • PDF version of this page (515K)

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...