Clinical Guidance

Some BAP1 missense pathogenic variants have been reported to be associated with Kury-Isidor syndrome . BAP1 pathogenic variants associated with BAP1-TPDS are mostly loss-of-function variants. Several missense variants have been reported in individuals presenting with BAP1-TPDS. As of November 19, 2024, there are eight missense variants (including seven in the BAP1 ubiquitin carboxyl-terminal hydrolase domain) that have been reported as pathogenic/ likely pathogenic in ClinVar. Some of these variants segregate with the BAP1 associated cancers in the family.

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Penetrance

The penetrance of 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, found a significantly lower prevalence of BAP1-related tumors in affected relatives compared to probands .

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Diagnostic Criteria

No diagnostic criteria have been published for 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

BAP1-TPDS should be suspected in probands with 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):

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Differential Diagnosis

Germline 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.

Table 2.

Genes to Consider in the Differential Diagnosis BAP1 Tumor Predisposition Syndrome

Cancer Type | Gene/ GeneticMechanism1 | Comments/References

UM |

BRCA1

BRCA2

MBD4

PALB2

| ,

MMe | CDKN2A2 |

CM |

CDKN2A

CDK4

MC1R

MITF | Pancreatic cancer is assoc w/CDKN2A pathogenic variants .

Hereditary RCC

| SDHB | See Hereditary Paraganglioma-Pheochromocytoma Syndromes.

FH

| Hereditary cutaneous leiomyomatosis, RCC, uterine leiomyomas (fibroids)

FLCN

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Management Guidelines

Clinical practice guidelines for BAP1 tumor predisposition syndrome (BAP1-TPDS) have been published . While there is largely consensus between the published guidelines, there are some differences possibly reflecting the location and health care systems in which the respective authors practice.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BAP1-TPDS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

BAP1 Tumor Predisposition Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

BIMT, CM, BCC,

/or onychopapilloma | • Full-body skin exam incl nails by dermatologist specializing in melanoma w/eval for subungual tumors

• Consider total body photography in those w/large number of lesions.

| Beginning at age ~18 yrs

UM | • Dilated eye exam baseline dilated fundus imaging

• Referral to ophthalmologist specializing in mgmt of UM (ocular oncologist) for any suspected lesion

| Beginning at age ~11-16 yrs or at puberty1

MMe | • Abdominal respiratory clinical exam w/further investigation for any clinical manifestations of MMe

• Abdominal MRI combined w/RCC screening2

Note: No consensus on screening modalities for MMe exists.2 | • Beginning at age 30 yrs

• Abdominal MRI combined w/RCC eval beginning at age 30 yrs

• Consider chest pelvic MRI as part of clinical trial.

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Clinical Guidance

Avoid the following:

• Arc welding

• Asbestos (including naturally occurring tremolite and erionite)

• Smoking

• Unnecessary and prolonged sun exposure

• Routine chest radiographs and CT examinations

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

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 National Cancer Institute (NCI)-sponsored trial (NCT01587352) using vorinostat in the treatment of metastatic UM is assessing BAP1 mutation status as a secondary outcome measure. Another NCI Phase II study is currently investigating the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment in individuals with BAP1-TPDS and subclinical, early-stage mesothelioma (NCT05960773).

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, international consensus recommendations for surveillance have not been established; however, several groups have proposed variations of the recommendations summarized in ) [, , , , ].

Table 5.

BAP1 Tumor Predisposition Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

BIMT, CM,

BCC, /or onychopapilloma

| • Full-body skin exam by dermatologist specializing in melanoma

• Biopsy of BIMT is not recommended unless lesions grow or change in shape or color.

| Annually beginning at age ~18 yrs

Consider total body photography in those w/large number of lesions. | As needed

UM | Surveillance by ophthalmologist w/dilated eye exam w/referral for pigmented lesions to ophthalmologist trained in diagnosis mgmt of ocular tumors (ocular oncologist) | Annually beginning at age ~11-16 yrs

Follow-up exam of pigmented lesions by ophthalmologist trained in diagnosis mgmt of UM (ocular oncologist) | As needed

MMe | • Clinical eval for manifestations of pleurisy (pleural inflammation), peritonitis, ascites, /or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, upper body face edema, abdominal pain, nausea, vomiting, /or constipation

• Note: (1) Avoid routine surveillance w/chest radiograph or CT.

Source: GeneReviews — "BAP1 Tumor Predisposition Syndrome"