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
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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|