This test analyzes the BAP1 gene, which is associated with BAP1 hereditary cancer predisposition syndrome. This condition, which is generally adult-onset, predisposes to the development of uveal melanoma, malignant mesothelioma, cutaneous melanoma, and renal cell carcinoma.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
BAP1 hereditary cancer predisposition syndrome is a recently described condition associated with an increased risk of several cancers, including uveal melanoma, malignant mesothelioma, cutaneous melanoma, and renal cell carcinoma.
Most BAP1-affected individuals also develop multiple benign cutaneous melanocytic neoplasms that resemble atypical Spitz tumors and dermal nevi but are clinically, histologically, and genetically distinct. A Spitz tumor is an uncommon benign melanocytic lesion composed of large epithelioid and/or spindled cells. It typically presents in childhood or adolescence as a dome-shaped, pink-red papule histologically resembling a melanoma but without the typical aggressive clinical behavior associated with adult melanoma.
BAP1-related cutaneous lesions can appear as early as adolescence, with multiple lesions developing over a lifetime. They are considered clinically stable with a low risk of malignancy; however, there have been reports of transformation to malignant melanoma. There is currently no agreement among pathologists on the classification or nomenclature of these distinctive BAP1 dermal tumors. They may be referred to as combined nevi, melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), atypical Spitz tumors (ASTs), combined Spitz tumors, or halo Spitz tumors.
These lesions may be used to screen individuals for BAP1 hereditary cancer predisposition syndrome because up to 72% of affected individuals have one or more. MBAITs typically occur earlier than the other associated malignancies, enabling identification of at-risk individuals, genetic testing, and the implementation of surveillance protocols.
While not everyone with a BAP1 pathogenic variant will manifest symptoms, up to 85% will develop cancer by age 65. The same variant can present differently, even among individuals within the same family. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.
|Cancer type||Cancer risk|
|Uveal melanoma||Up to 31%|
|Renal cell carcinoma||10%|
When malignancies occur in a setting of hereditary BAP1 pathogenic variants, they tend to have an earlier age of onset, be more aggressive, and metastasize compared to individuals with sporadic versions of the same types of cancer. The exception to this is malignant mesothelioma, which is typically less aggressive and has a more favorable outcome in individuals with BAP1 hereditary cancer predisposition syndrome.
Inheritance follows an autosomal dominant pattern. Most cases are inherited but the rate of spontaneous de novo mutations is unknown.
The prevalence of BAP1 hereditary cancer predisposition syndrome is currently unknown and appears to be rare.
BAP1 gene analysis may be considered in individuals with:
For management recommendations, please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|