• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The FLCN gene is associated with autosomal dominant Birt-Hogg-Dubé (BHD) syndrome (MedGen UID: 91070).

Order single gene


Order this gene as a single gene test.

Order a test

Invitae tests that include this gene:

The FLCN gene, which encodes the folliculin protein, is thought to be a tumor suppressor and may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways, which play an important role in the regulation of cell growth, proliferation, differentiation, motility, survival, metabolism and protein synthesis.

FLCN Birt-Hogg Dube
MedGen UID: 91070

Clinical condition
Birt-Hogg-Dubé syndrome (BHD) is a highly variable condition characterized by the development of cutaneous lesions, renal tumors, pulmonary cysts, and/or spontaneous pneumothorax (PMID: 25519092, 27514594, 26334087).

The hallmark skin findings associated with BHD are characterized as a triad of fibrofolliculomas,  trichodiscomas, and acrochordons (also known as skin tags)(PMID: 25519092, 27514594). Fibrofolliculomas are benign, painless hair follicle tumors that develop after puberty and are present in over 85% of affected adults over age 25 (PMID: 27514594, 26334087). These are firm, white or flesh-colored papules with a dome-shaped appearance measuring approximately 2 to 4 mm in diameter (PMID: 25519092, 26334087). Fibrofolliculomas primarily develop on the face, neck, and upper torso, and sometimes form in clusters, coalescing into a plaque (PMID: 25519092, 26334087, 27514594).

Trichodiscomas are tumors of the hair disks (PMID: 25519092). Trichodiscomas are essentially histologically and clinically indistinguishable from angiofibromas and the term trichodiscoma is typically used when related to BHD. In addition, tricodisocmas have been suggested to be part of the same morphologic spectrum as fibrofolliculomas (PMID: 26334087, 27514594). Sectioning these lesions in different planes appears to result in artificial differences in histologic variation (PMID: 26334087).

Perifollicular fibromas and angiofibromas are also associated with BHD. Other less common skin findings include lipomas, angiolipomas, oral mucosal papules and fibromas, melanoma, and collagenoma (PMID: 25519092, 27514594). The onset of skin lesions is typically during the third or fourth decade of life and typically increase in size and number with age. Later onset is correlated with a milder skin phenotype and women are often less affected than men.

Pulmonary involvement is common in BHD, manifesting as pulmonary cysts and recurrent pneumothoraces (PMID: 27514594). Multiple and bilateral pulmonary cysts are seen in 77-89% of affected individuals, most often identified in the fourth and fifth decades of life (PMID: 27514594, 25519092). The number of cysts is highly variable with sizes ranging from a few millimeters to 2 cm (PMID: 25519092, 26334087). They are typically subpleural in distribution and often irregularly shaped, with sharply demarcated, thin walls (PMID: 26334087, 25519092). BHD-related pulmonary cysts are  also typically located in the basilar and mediastinal regions of the lung, helping distinguish them from other cystic lesions such as apical blebs and bullae (PMID: 25519092, 26334087, 27514594). BHD-related pulmonary lesions are not associated with neoplasia, inflammation, or fibrosis (PMID: 25519092, 27514594). Individuals with BHD typically function well in the absence of pneumothorax (PMID: 27514594). Clinically, they are often asymptomatic, with pulmonary function tests that are typically normal or only minimally impaired (PMID: 25519092, 27514594). Some symptoms can include dyspnea, cough, or angina, which are more often seen in older individuals and those with more severe lung involvement (PMID: 25519092). The role of cigarette smoking remains unclear, although more severe cystic changes have been reported in smokers with BHD compared to nonsmokers in a small case series (PMID: 27514594, 25519092).

BHD is also associated with a 50-fold increased risk of spontaneous pneumothorax compared to the general population, correlating inversely with age (PMID: 25519092, 27514594, 26334087). Approximately 24-38% of individuals BHD experience at least one pneumothorax, with a median age of 38 years; 75% of affected individuals will experience a recurrent event (PMID: 27514594, 26334087). The number, size, and volume of pulmonary cysts appear to be risk factors for pneumothorax; however, events have been reported in the absence of radiographically detectable cysts (PMID: 27514594, 25519092). Pneumothorax may be the only manifestation of BHD cysts (PMID: 25519092). Some studies have suggested that 5-10% of apparently sporadic pneumothoraces may be due to underlying BHD (PMID: 27514594). Lower atmospheric pressure when flying in a pressurized cabin may potentially result in gas expansion within pulmonary cysts, causing a pneumothorax (PMID: 27514594). In general, air travel is considered safe; however, it has been suggested that affected individuals not board an airplane with unexplained chest pain or shortness of breath (PMID: 27514594). Likewise, those with BHD are advised against scuba diving, as changes in ambient atmospheric pressure could predispose to the develop pneumothoraces (PMID: 27514594).

The prevalence of malignant renal tumors in BHD is 12-34%, with an average age of onset between the ages of 46-52 years (PMID: 25519092, 26334087, 27514594). These lesions tend to be bilateral, multifocal, and slow-growing (PMID: 26334087, 27514594). While metastasis can occur, it is relatively infrequent (PMID: 26334087, 27514594). Renal cancer types include (PMID: 25519092, 26334087, 27514594, 18234728):

  • hybrid oncocytic tumor (hybrid of oncocytoma and chromophobe histologic cell types) (50-67%)
  • chromophobe renal cell carcinoma (23-35%)
  • clear cell renal carcinoma (9%)
  • renal cell oncocytomas (3-5%)
  • papillary renal carcinoma (2%)

Benign renal cysts have been documented in BHD, including a French study which identified renal cysts without carcinoma using CT, MRI, and ultrasound in 45% of affected individuals (PMID: 19785621), however the exact prevalence in comparison to the general population is currently unclear (PMID: 25519092). Renal angiomyolipoma has also been observed (PMID: 25519092).

Other findings:
Other less commonly reported findings associated with BHD include lipoma, multinodular goiter, parathyroid adenoma, parotid-gland adenoma, neural tissue tumor, trichoblastoma, connective tissue nevus, focal cutaneous mucinosis, and cutaneous leiomyoma (PMID: 25519092, 26334087).

There is also preliminary evidence suggesting an association between pathogenic variants in FLCN and colorectal cancer, and this gene is therefore available as a “preliminary evidence” gene on Invitae’s Colorectal Cancer Panel (PMID: 20522427, 20392993, 26334087). Preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available and therefore clinicians may continue to order these preliminary evidence genes.

Gene information
FLCN is believed to be a tumor suppressor gene involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways (UniProtKB – Q8NFG4 (FLCN_HUMAN). http://www.uniprot.org/uniprot/Q8NFG4. Accessed March 2018.)

FLCN has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant.

Due to the complexity of BHD, affected individuals are best served by seeking care through a multidisciplinary clinic with experience treating this condition. Early diagnosis allows immediate implementation of surveillance and management. While there is not a consensus on standard guidelines for surveillance, the following have been recommended, in addition to annual physical examinations (PMID: 25519092, 27514594, 26334087):

Skin (PMID: 25519092, 27514594):

  • No specific medical treatment is indicated for BHD-related cutaneous lesions
  • Occasionally, intervention may be considered for disfiguring lesions
    • Surgical removal for solitary fibrofolliculomas
    • Electrodessication for removing multiple lesions
      • With any dermatologic  intervention, patients should consider the high recurrence of lesions and the risk of complications such as scarring, inflammation, hypopigmentation, and hyperpigmentation

Pneumothorax prevention and treatment are the primary goals (PMID: 27514594):

  • Baseline high-resolution chest CT
  • Regular follow-up with pulmonologist, including periodic measurement of pulmonary function if lung function is impaired
  • Education regarding increased risk of spontaneous pneumothorax, and associated signs and symptoms
  • Avoidance of cigarette smoking and scuba diving
  • Caution about the increased risk of pneumothorax associated with air travel
    • In general, air travel is considered safe for most with BHD
  • Regular immunizations are recommended as well as pneumococcal and annual influenza vaccinations
  • Consideration of pleurodesis for treatment of the first pneumothorax

Kidneys (PMID: 26334087, 27514594):

  • Abdominal imaging at least every 36-48 months, beginning at age 20
    • Abdominal CT or MRI with contrast is preferred, as renal ultrasonography may not detect small lesions
      • MRI imaging is preferred to reduce long-term radiation exposure
  • Imaging intervals are determined by the size and growth rate of any identified renal tumors
    • Surgical intervention when the largest tumor reaches 3 cm in size
    • Nephron-sparing resection is advised to preserve renal function

mTOR inhibitors have been shown to be effective in managing some BHD-associated renal cancers (PMID: 26334087). The FDA has approved several agents that target the mTOR pathway to treat metastatic cases (PMID: 26334087). In addition to targeting the mTOR pathway, studies have uncovered other potential targets and therapeutic approaches for BHD-associated renal cancer that appear promising (PMID: 26334087).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a pathogenic variant in FLCN is present. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding FLCN is constantly evolving and more clinically relevant data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Review date: March 2018

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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
FLCN NM_144997.5