This test analyzes the SMARCB1 and SMARCA4 genes. Pathogenic variants in these genes are associated with rhabdoid tumor predisposition syndrome (RTPS).
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.
Rhabdoid tumors are rare, aggressive childhood cancers that most often develop in the kidney (malignant rhabdoid tumor, MRT) and central nervous system (atypical teratoid/rhabdoid tumor, AT/RT). These lesions can occur spontaneously or as part of hereditary rhabdoid tumor predisposition syndrome (RTPS). In comparison to sporadic isolated rhabdoid tumors, the syndromic form is associated with an increased risk of developing multiple tumors at younger ages and schwannomas (benign nerve sheath tumors) that present primarily in adulthood.
There are two subtypes of RTPS. RTPS1 is caused by pathogenic variants in SMARCB1 and RTPS2 is caused by pathogenic variants in SMARCA4. Most cases are due to SMARCB1, but the features of RTPS1 and RTPS2 are clinically indistinguishable. Some individuals with pathogenic SMARCA4 variants may present with small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT).
Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, though most individuals with a pathogenic variant will never develop a rhabdoid tumor. The same genetic variant can present differently, even among family members. The lifetime cancer risks for individuals with RTPS are currently unclear.
RTPS is inherited in an autosomal dominant pattern, but it is uncommon for the condition to actually be inherited from a parent. Most cases of RTPS occur as the result of a spontaneous de novo mutation.
Rhabdoid tumors are very rare. Of all brain tumors diagnosed in children, approximately 1.5%-2.1% are rhabdoid tumors (AT/RT). Malignant rhabdoid tumors (MRT) occur in the kidney and are the the cause of 0.9%-2% of all renal cancers. Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), which is also known as malignant rhabdoid tumor of the ovary (MRTO), accounts for less than 1% of all ovarian cancer. Most cases of rhabdoid tumors are isolated and non-syndromic; an estimated 30%-35% of cases are due to RTPS.
Genetic testing for RTPS is reasonable to consider for any individual with a personal and/or family history of any of the following:
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|