Invitae Familial Gastrointestinal Stromal Tumor Syndrome Panel


Test description

This test analyzes genes associated with familial gastrointestinal stromal tumor syndrome (GIST), which is a rare hereditary gastrointestinal cancer predisposition syndrome.

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.

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Primary panel (7 genes)


SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.

Alternative tests to consider

The genes on this panel can also be ordered as part of broader panels to test for different types of hereditary cancer. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.

  • familial gastrointestinal stromal tumors (GIST)
  • neurofibromatosis type 1 (NF1)
  • Carney-Stratakis syndrome

Gastrointestinal stromal tumors (GISTs) account for less than 1% of all gastrointestinal tumors. Approximately 5,000 new cases are diagnosed in the United States each year. GISTs are typically adult-onset sarcomas that may be either benign or malignant and that can occur anywhere along the GI tract, which includes the esophagus, stomach, gallbladder, liver, small intestine, colon, rectum, anus, and lining of the gut. They arise from a specific type of cell called interstitial cells of Cajal (ICC), which line the walls of the GI tract. More than half of GISTs start in the stomach. The next-largest proportion of cases starts in the small intestine. The third-largest proportion starts in the omentum. The fourth-largest proportion starts in the peritoneum.

Sporadic cases of GIST typically develop only a single tumor while familial cases of GIST can present with multiple tumors, dysphagia, achalasia, and skin findings that include hyperpigmentation and urticaria pigmentosa. GIST is also a feature of neurofibromatosis type 1 and Carney-Stratakis syndrome, an autosomal dominant condition characterized by the development of GIST and/or paragangliomas.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, GIST can present differently, even among family members. Although there is an increased risk for GIST associated with the genes on this panel, the risk for malignant GIST is currently unclear.

These genes collectively account for approximately 5%-7.5% of all GISTs. These tumors have a tendency to appear in children and young adults.

Pathogenic variants in PDGFRA is associated with GIST as well as inflammatory fibroid bowel polyps. GIST appears to be the only tumor with malignant potential associated with this gene, although the data are emerging.

Most cases of familial GIST are due to pathogenic variants in the KIT. Some affected individuals may also present with skin hyperpigmentation, dysphagia, and urticaria pigmentosa, which is a mastocytosis disorder that causes brown or salmon-colored itchy patches to develop on the skin.

Up to 25% of individuals with neurofibromatosis type 1 develop GIST. Many cases are asymptomatic and are found incidentally. Symptomatic GISTs in individuals with NF1 are typically multiple, diagnosed before age 50, and found in the small intestine and stomach.

The genes in the Invitae Familial Gastrointestinal Stromal Tumor Syndrome Panel are associated with familial GIST, but the overall percentage of hereditary GIST cases attributed to these genes is currently unclear. Inclusion of several GIST-related genes is expected to increase the clinical sensitivity of this test.

Familial GIST is inherited in an autosomal dominant pattern.

Testing for familial GIST should be considered in individuals with a personal and/or family history of one or more of the following:

  • one or more GISTs, particularly if it is early onset (<50 years of age)
  • GIST and another, unrelated cancer in the same individual
  • several close relatives with GIST
  • GIST and unusual skin findings (hyperpigmentation, urticaria pigmentosa, axillary/inguinal freckling)

The American College of Medical Genetics has proposed guidelines to determine which individuals are candidates for familial GIST analysis:

  1. Antonescu, CR. Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models. Semin Diagn Pathol. 2006; 23(2):63-9. doi: 10.1053/j.semdp.2006.08.003. PMID: 17193819
  2. Bardella, C, et al. SDH mutations in cancer. Biochim. Biophys. Acta. 2011; 1807(11):1432-43. doi: 10.1016/j.bbabio.2011.07.003. PMID: 21771581
  3. Carballo, M, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am. J. Med. Genet. A. 2005; 132A(4):361-4. doi: 10.1002/ajmg.a.30388. PMID: 15742474
  4. GIST Support International, Genetic Factors in GIST. Accessed June 2015.
  5. Giuly, JA, et al. Von Recklinghausen disease and gastrointestinal stromal tumors. Am. J. Surg. 2003; 185(1):86-7. doi: 10.1016/s0002-9610(02)01111-x. PMID: 12531453
  6. Gorgel, A, et al. Coexistence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in three cases of neurofibromatosis type 1 (NF1) with a review of the literature. Intern. Med. 2014; 53(16):1783-9. doi: 10.2169/internalmedicine.53.2012. PMID: 25130111
  7. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  8. Hartmann, K, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005; 129(3):1042-6. doi: 10.1053/j.gastro.2005.06.060. PMID: 16143141
  9. Kleinbaum, EP, et al. Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor. Int. J. Cancer. 2008; 122(3):711-8. doi: 10.1002/ijc.23137. PMID: 17943734
  10. Lodish, MB, Stratakis, CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract. Res. Clin. Endocrinol. Metab. 2010; 24(3):439-49. doi: 10.1016/j.beem.2010.02.002. PMID: 20833335
  11. National Library of Medicine, Genetics Home Reference: Gastrointestinal Stromal Tumor. Accessed June 2015.
  12. Postow, MA, Robson, ME. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res. 2012; 2(1):16. doi: 10.1186/2045-3329-2-16. PMID: 23036227
  13. Ricci, R, et al. PDGFRA-mutant syndrome. Mod. Pathol. 2015; 28(7):954-64. doi: 10.1038/modpathol.2015.56. PMID: 25975287
  14. Wang, YM, et al. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J. Gastroenterol. 2015; 21(8):2303-14. doi: 10.3748/wjg.v21.i8.2303. PMID: 25741136
  15. Woźniak, A, et al. Rectal gastrointestinal stromal tumors associated with a novel germline KIT mutation. Int. J. Cancer. 2008; 122(9):2160-4. doi: 10.1002/ijc.23338. PMID: 18183595
  16. Zöller, ME, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997; 79(11):2125-31. doi: 10.1002/(sici)1097-0142(19970601)79:11<2125::aid-cncr9>;2-n. PMID: 9179058
  17. de, Raedt, T, et al. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology. 2006; 131(6):1907-12. doi: 10.1053/j.gastro.2006.07.002. PMID: 17087943

Assay and technical information

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
KIT NM_000222.2
NF1 NM_000267.3
PDGFRA NM_006206.4
SDHA* NM_004168.3
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3

SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.