Hereditary Leiomyomatosis and Renal Cell Carcinoma

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by mutations in the FH gene and is  characterized by an increased risk of benign tumors of the skin and uterus (leiomyomata) as well as kidney cancer.

Note: Inheriting two FH mutations (one from each parent) causes a different hereditary condition, called Fumarase Hydratase deficiency (FHD). This rare autosomal recessive condition impacts infants and typically causes hypotonia, seizures, and cerebral atrophy

Quick Reference
Test Code: 6301 Test Name: FH seq and del/dup TAT 14-21 days Gene: 1
Test Code: 6302 Test Name: FH specific site analysis TAT 7-14 days Gene: 1

Ordering Options

We now offer single site analysis (SSA) at no additional cost to family members

following single gene or panel testing* of the first family member (proband) within 90 days of the original Ambry report date.

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*excludes Secondary Findings and SNP Array tests

Why Is This Important?

  1. Option to modify age, frequency, and type of cancer screening, as needed
  2. Identify at-risk family members

When To Consider Testing

Testing is indicated for those with any of the following findings:1 

  • Multiple cutaneous leiomyomas (with at least one histologically confirmed leiomyoma) without a family history of HLRCC
  • A single cutaneous leiomyoma with a family history of HLRCC
  • One or more tubulo-papillary, collecting-duct, or papillary type 2 renal tumors/cancers with or without a family history of HLRCC
  • A family history of a FH mutation 

Mutation Detection Rate

Ambry's FH analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Test Description

FH coding exons 1-10 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-10. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of FH using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).


1. Pithukpakorn M, et al. Hereditary Leiomyomatosis and Renal Cell Cancer. GeneReviews. S. University of Washington, Editor. 2006: Seattle (WA)

2. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.

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