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FH (fumarate hydratase) – genetic testing

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This protocol covers testing for dominant pathogenic variants in the fumarate hydratase (FH) gene which are associated with the familial tumour syndrome, hereditary leiomyomatosis and renal cell carcinoma (HLRCC). This protocol does not cover pathogenic variant testing for the recessive metabolic disorder fumarate hydratase deficiency.

1. An individual with clinical features suggestive of HLRCC:

  1. renal cell carcinoma (RCC) with histopathology consistent with HLRCC*r and/or FH deficient on immunohistochemistry or
  2. multiple cutaneous leiomyomas (at least one histopathologically confirmed) or
  3. uterine leiomyoma with atypical FH-associated pathology and/or which is FH deficient on immunohistochemistry.r

2. An individual with two or more of the following:

  1. a single cutaneous leiomyoma (histopathologically confirmed)
  2. multiple symptomatic uterine leiomyomas
  3. RCC with HLRCC-associated pathology (expert pathology review may be required)*
  4. AND a first-degree relative with a clinical feature of HLRCC.

If there are two women affected with symptomatic uterine leiomyomas, then another HLRCC feature must also be present to consider HLRCC.

3. First degree relative of a child with fumarate hydratase deficiency due to biallelic pathogenic variants in the FH gene.

4. Where a known germline pathogenic variant identified in a relative.*

5. 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. 

*HLRCC-associated RCCs are predominantly high-grade with a papillary growth pattern. However, HLRCC-associated RCCs have been described to show tubulopapillary, tubulocystic, tubular, solid and cystic areas and may overlap morphologically with collecting duct carcinomas. Multiple architectural patterns, including sarcomatoid and rhabdoid components, may be seen within the same tumour. Large nuclei with prominent orangiophilic or eosinophilic nucleolus surrounded by a clear halo are often observed.rr

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

  • clinical examination for detection of multiple cutaneous leiomyomas with biopsy of at least one lesion
  • consider expert pathology review of renal tumour, especially for metastatic non-clear cell RCC
  • FH immunohistochemistry and S-(2-succino)cysteine immunohistochemistry (if available).

There is no data on the frequency of FH pathogenic variants in unselected, population-based series with regards to the other manifestations of HLRCC including: multiple cutaneous leiomyomas, uterine leiomyomas or HLRCC-associated RCC. Data regarding the probability of detecting a heritable pathogenic variant is only available from studies where patients have been ascertained on the basis of presenting with manifestations clinically suggestive of HLRCC (probands) and then cascade testing of at-risk relatives (carriers).

FH immunohistochemistry is highly specific but not particularly sensitive for FH inactivation in RCC.r FH immunohistochemistry has not been found to reliably detect FH inactivation in uterine leiomyomas.r 

There is no data on the frequency of de novo FH pathogenic variants.

Factors Probability of detecting a heritable pathogenic variant
Isolated HLRCC-associated RCC before age 40 or HLRCC-associated RCC with clinical features suggestive of HLRCC at any age >10%r
Metastatic non-clear cell RCC 9.5%r
Individual with uterine leiomyoma with atypical histopathology and FH deficiency on immunohistochemistry 50%-60%r
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

Testing is NOT indicated in individuals with:

  • a single cutaneous leiomyoma without additional clinical features of HLRCC
  • multiple uterine leiomyomas without additional clinical features of HLRCC
  • multiple leiomyomas in organs other than skin or uterus.

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 FH 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

 FH (Hereditary leiomyoma renal cell carcinoma) - risk management
Variant of uncertain significance

Surveillance may still be required depending on the clinical and family history

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   FH (Hereditary leiomyoma renal cell carcinoma) - 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

Harrison, W. J., J. Andrici, F. Maclean, et al. 2016. "Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings." Am J Surg Pathol 40(5):599-607.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

Merino, M. J., C. Torres-Cabala, P. Pinto, et al. 2007. "The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome." Am J Surg Pathol 31(10):1578-1585.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterized by the development of cutaneous and uterine leiomyomas as well as renal tumors. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene. The histology of the renal cancers has not been well described or illustrated because of the newness of the syndrome. We reviewed 40 renal tumors resected from 38 patients belonging to HLRCC families with proven fumarate hydratase germline mutation. Patients ranged in age from 17 to 75 years of age. Tumors were unilateral in all but 2 cases. The size of the tumors varied between 2.3 and 20 cm and there was no laterality preference. Several different architectural patterns were recognized: papillary (25 cases), tubulo-papillary (8 cases), tubular (2 cases), and solid (1 case). Mixed patterns were also present in 4 cases. The most important histologic feature of these neoplasms, which we believe to be the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Immunohistochemical studies did not provide a specific marker for these tumors, however, loss of heterozygosity at 1q32 and 1q42-44 was frequently found. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes. At the moment, morphology is the best tool to recognize these tumors. Proper diagnosis of this syndrome by the pathologist may assist in early detection of these tumors.

Version 6

Date Summary of changes
20/02/23

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

  • Target population: 
    • Added "where a specific pathogenic variant has been identified on somatic tumour testing *"
    • Added "*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective."
  • Circumstances in which testing is not indicated:
    •  Removed "A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where: 
      • a known pathogenic variant has been identified in a relative
      • a specific pathogenic variant has been identified on somatic tumour testing."
  • Testing methods:
    • Added "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."
    • Removed "e.g. MLPA, Sanger sequencing"
  • Result interpretation:
    • Template sentence added.

Version increased to V.6. 

Version 5

Date Summary of changes
22/02/21

Protocol reviewed at October 2019 reference committee meeting. Discussion continued via email. Approved for publication with the following changes made:

  • Target population: many changes
  • Investigations before genetic testing: 'FH immunohistochemistry and S-(2-succino)-cysteine immunohistochemistry (if available)' added
  • Probability of a heritable pathogenic variant: references updated, 'Individual with multiple histopathologically confirmed cutaneous leiomyomas' and 'Individual with multiple symptomatic uterine leiomyomas before age 40 with clinical features suggestive of HLRCC' and corresponding probability percentages deleted; 'Metastatic non-clear cell RCC - 9.5%' and 'Individual with uterine leiomyoma with atypical histopathology and FH-deficiency on immunohistochemistry - 50%-60%' plus references added to table

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

  • "Mutation" changed to "pathogenic variant" and definition of "pathogenic variant" added as a pop-up, and ‘unclassified variant’ changed to ‘variant of uncertain significance’ throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs
  • 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 "25% or 50%" to "Up to 50%"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording added
  • Result interpretation: table format updated. Reference databases added. Template sentences added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: section deleted

Version number changed to V.5. Review in 2 years.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 4

Date Summary of changes
23/01/2015

New protocol discussed at March 6, 2013 cancer genetics reference committee meeting.  Discussions continued via email, protocol approved for publication Jan 23 2015.
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.
09/11/2017  Protocol review presented at May Cancer Genetics reference committee meeting. Discussion continued via email, protocol approved for publication November 9, 2017. Version number changed to V.3. 
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the fumarate hydratase gene' to 'FH (fumarate hydratase) 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/1420

31 May 2023