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FLCN (folliculin) – genetic testing

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Heritable FLCN testing should be considered in individuals:

  • with a suspected diagnosis of Birt-Hogg-Dubé syndrome (BHD)
  • where a known germline pathogenic variant is identified in a relative*
  • where a specific pathogenic variant has been identified on somatic tumour testing*

*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective. 

Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the FLCN gene:

  • excision and histological confirmation of suspicious skin lesions
  • chest CT
  • renal imaging - preferably MRI with contrast.

There is no data on the frequency of germline FLCN pathogenic variants in unselected, population-based series of cancer of the kidney, however the incidence is low. Data are only available from studies where patients have been ascertained on the basis of presenting with manifestations clinically suggestive of BHD (probands) and then cascade testing of at risk relatives (carriers). The frequency of heritable pathogenic variants in FLCN is dependent on kidney cancer pathology (hybrid oncocytic tumours, oncocytomas and chromophobe renal cancers in particular) and the presence of pulmonary and dermatologic features of BHD.

Factors Probability of detecting a heritable pathogenic variant
Clinical features satisfying BHD consortium criteria 88%r*^
Multiple basally located lung cysts of undetermined cause 33%r
Primary spontaneous pneumothorax  5-10%r
Renal tumour < 1%r
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

* Sequencing only
^ A number of large deletions in folliculin have been identified in families who had been clinically diagnosed with BHD but had not been shown to have a pathogenic variant using DNA sequencing techniquesr

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

A range of testing methodologies are needed to identify pathogenic changes in the FLCN gene including:

  • sequencing 
  • copy number analysis 

Information about DNA tests and testing laboratories is available from: 

A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour. 

If a decision is made to test this gene as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.

If this gene is tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology should be considered.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour samples may be indicated to assess for mosaicism. 

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

UMD

LOVD

 FLCN (Birt-Hogg-Dubé) - risk management
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered
No reportable variant   Identify other genes for which a pathogenic variant search could be considered
Predictive testing
Family pathogenic variant identified   FLCN (Birt-Hogg-Dubé) - risk management
Family pathogenic variant not found   Screening based on revised risk estimate

If a pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

If a mosaic pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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Bibliography

Schmidt, L. S. and W. M. Linehan. 2015. "Molecular genetics and clinical features of Birt-Hogg-Dube syndrome." Nat Rev Urol 12(10):558-569.

Birt-Hogg-Dube (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFbeta signalling, PGC1alpha-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease.

Dow, E. and I. Winship. 2016. "Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex." Am J Med Genet A 170(12):3323-3326.

Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disease characterised by benign cutaneous lesions, pulmonary cysts, and an increased risk of renal tumors. This rare condition is due to a mutation in the folliculin (FLCN) gene on chromosome 17q11.2, which has a role in the mechanistic/mammalian target of rapamycin (mTOR) signaling pathway of tumorigenesis. This case illustrates a patient with BHD and a renal angiomyolipoma, a neoplastic lesion not usually associated with BHD but common in Tuberous Sclerosis Complex (TSC). There is both clinical and molecular overlap between BHD and TSC, which may arise from similarities in function of the TSC and FLCN proteins in the mTOR pathway; this case further demonstrates this potential correlation. (c) 2016 Wiley Periodicals, Inc.

Version 7

Date Summary of changes
17/07/2023

Document reviewed electronically by cancer genetics reference committee. Approved for publication with the following changes made:

  • Document updated to align with the 2023 eviQ cancer genetics genetic testing template changes
  • Probability of a heritable pathogenic variant: "Renal tumour" added to table

Version increased to V.7. Review in 2 years. Approved on 17/07/2023, published on 02/08/2023.

Version 6

Date Summary of changes
09/12/2020

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template:

  • Related pages: added link to "Guide for health professionals ordering genetic testing". Removed link to "Pre-test counselling"
  • Probability of a heritable pathogenic variant: last row of table - probability changed from "50% or 25%" to "Up to 50%"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording updated
  • Result interpretation: table format updated. Reference databases added. Template sentence added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: removed link to European Molecular Genetic Quality Network
  • Version number increased to V.6.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 5

Date Summary of changes
03/10/2019

Protocol reviewed at May 2019 reference committee meeting. Approved for publication with the following changes made: 

  • Target population:
    • "clinical diagnosis" changed to "suspected diagnosis" and new ACI (ID 3669 - Criteria suspicious for Birt-Hogg-Dubé syndrome (BHD)) developed to supplement protocol
    • "multiple bilateral basally located lung cysts with no other apparent cause" removed 
  • Probability of a heritable pathogenic variant: reviewed and updated
  • Protocol template changes applied
  • "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up.

Protocol version number increased to V.5. Review in 2 years
19/11/2019 "Unknown significance" changed to "uncertain significance" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs.

Version 4

Date Summary of changes
21/04/2015 Protocol presented at Aug 2012 RCM.  Discussions continued over email and document approved for publication.
30/09/2015 Sentence added to Genetic Testing protocol template: " if a decision is made to test this gene(s) as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility".
31/05/2017 Transferred to new eviQ website. Version number changed to V.2.
10/11/2017  Protocol presented at May 2017 RCM. Discussion continued over email and document approved for publication. Version number changed to V.3.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the folliculin (FLCN) gene' to 'FLCN (folliculin) genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.4.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1283

04 Dec 2023