HLRCC — a hereditary cancer syndrome where renal cell carcinoma metastasizes at remarkably small sizes, making standard active surveillance protocols dangerous and requiring immediate surgical intervention for any suspicious renal lesion.
Whole genome sequencing identifies all FH (fumarate hydratase) variants — providing the molecular diagnosis that fundamentally changes renal mass management from 'watch and wait' to 'operate immediately.'
Hereditary Leiomyomatosis and Renal Cell Cancer
Hereditary leiomyomatosis and renal cell cancer (HLRCC, Reed syndrome) is an autosomal dominant cancer predisposition syndrome caused by heterozygous pathogenic variants in FH (fumarate hydratase, chromosome 1q43). FH is a tumor suppressor functioning in the tricarboxylic acid (TCA) cycle — FH deficiency causes fumarate accumulation, which inhibits prolyl hydroxylases and stabilizes HIF (hypoxia-inducible factor), driving a pseudohypoxic oncogenic program. HLRCC produces three clinical features: cutaneous leiomyomas (painful skin nodules in ~76%), uterine leiomyomas (fibroids, often symptomatic before age 30 in ~77% of women), and renal cell cancer (~15-25% lifetime risk).
The renal cell cancer in HLRCC is type 2 papillary RCC — and it is uniquely aggressive. Unlike the indolent RCC seen in VHL disease or other hereditary RCC syndromes, HLRCC-associated RCC can metastasize when the primary tumor is only 1-2 centimeters. This biological aggressiveness fundamentally changes the management paradigm: standard active surveillance protocols for small renal masses (≤4cm, which are appropriate for most sporadic RCC) are DANGEROUS in HLRCC. Any solid renal lesion in an HLRCC patient should be considered potentially aggressive and managed with prompt surgical excision, not observation.
HLRCC is underdiagnosed because the individual features — skin bumps and uterine fibroids — are common in the general population and are often managed by dermatologists and gynecologists without considering the hereditary cancer context. The painful cutaneous leiomyomas (characteristically cold-sensitive) are the most specific clinical clue. Early-onset uterine fibroids requiring hysterectomy before age 30 should also prompt FH evaluation. Molecular FH diagnosis triggers the specific HLRCC renal surveillance protocol (annual high-quality MRI, not ultrasound) that cannot be implemented without knowing the patient carries an FH pathogenic variant.
Active surveillance of small renal masses — standard of care for most RCC — is CONTRAINDICATED in HLRCC. The aggressive biology means that even 1-2cm HLRCC tumors can metastasize. Any solid renal lesion requires prompt surgical excision.
Standard RCC management protocols assume indolent biology. FH-associated RCC has aggressive biology that violates this assumption. Molecular FH diagnosis triggers the surveillance and treatment protocol that prevents metastatic disease.
Standard active surveillance kills HLRCC patients — molecular FH diagnosis changes the surgical urgency for renal masses
For sporadic small renal masses (≤4cm), active surveillance with imaging follow-up is an accepted management strategy because most are low-grade and slow-growing. In HLRCC, applying this same surveillance approach to a 2cm type 2 papillary RCC risks allowing metastatic spread before the surveillance protocol triggers intervention. Multiple HLRCC patients have developed metastatic disease from primary tumors that would have been managed with surveillance under standard RCC protocols. Molecular FH diagnosis before any renal mass is detected enables the HLRCC-specific protocol: annual MRI surveillance and immediate surgery for any solid lesion.
Painful skin bumps + early fibroids = consider HLRCC. Most dermatologists and gynecologists do not make this connection
Cutaneous leiomyomas (painful, cold-sensitive skin nodules typically on the trunk and extremities) and early-onset uterine leiomyomas are individually common — but their combination, particularly with a family history of kidney cancer, should prompt FH evaluation. Many HLRCC families are identified only after a member develops metastatic RCC — by which point the cancer is often incurable. WGS performed for any indication can identify FH variants incidentally, triggering the renal surveillance program that would have detected the cancer at a curable stage.
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Traditional genetic testing looks at narrow sets of genes, missing most parts of your genome. We sequence your full genome — every gene and every region between genes.
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A patient had spent decades in the UK healthcare system without a diagnosis. Dante data, accepted by NHS clinical teams at Queen Elizabeth University Hospital Glasgow, identified Noonan Syndrome and a RUNX1 leukemia-associated variant that had gone undetected. After 40 years, they finally had an answer.
A complete read delivers a complete picture.
A patient came to Dante to investigate periodic paralysis. Reading the complete genome identified a concurrent hereditary cardiac finding — Brugada syndrome — that their doctor confirmed with an ECG. The result also explained a family member's unresolved cardiac history. One test. Every answer in it.
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Jennifer sequenced her genome with Dante two years before her breast cancer diagnosis. When treatment began, Dante's pharmacogenomics data showed her prescribed chemotherapy would cause serious adverse effects. Her doctor selected an alternative — and she started effective treatment from day one.
Every genetic question deserves a complete answer.
Whether you are searching for answers today or protecting your health for tomorrow, a complete read of your entire genome is the only place to start.
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Your genome contains inherited variants associated with medical conditions like cardiac, cancer, and neurological. We read all of them — with the clinical depth to give the result meaning.
Learn more →When traditional lab tests say you're fine. And you know you're not.
Standard diagnostic tests check for a pre-selected set of answers. We sequence your full DNA — including parts that no test was designed to check. If the answer is in your genome, we will help you find it.
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Your genes determine which treatments are most likely to work — and which are not. We give your doctor the tools and insights to inform your treatment plan.
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Some people don't wait for a diagnosis or a family history to act. Whole genome sequencing gives you the complete genetic picture now — so you and your doctor can make informed decisions before anything becomes urgent.
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Common questions about whole genome sequencing.
What is the difference between whole genome sequencing and a targeted genetic test?
Targeted genetic tests — including standard hereditary cancer panels — read a pre-defined list of known variants in a specific set of genes. They are designed to find what they already know to look for. Whole genome sequencing reads your entire genome: all 6 billion base pairs, every gene, every region between genes. A Mayo Clinic study published in JAMA Oncology found that standard testing guidelines missed more than half of patients with inherited cancer mutations. Genome Test does not have a fixed list.
What will I receive when my results are ready?
Your Dante Genome delivers 200+ physician-ready reports organized by clinical category — hereditary cancer, cardiac conditions, rare diseases, pharmacogenomics, carrier status, and more. Reports are delivered to your secure Genome Manager and are formatted for direct clinical use. Your genome data is permanently retained and re-analyzed automatically as science advances.
What happens if a clinically significant variant is found?
If a pathogenic or likely-pathogenic variant is identified, it will be clearly flagged in your physician-ready report with clinical context, published evidence, and recommended next steps. We recommend sharing any clinically significant finding with your physician or a genetic counselor, who can guide decisions about surveillance, risk reduction, or cascade testing for family members.
How is this different from a consumer DNA test like 23andMe or AncestryDNA?
Consumer DNA tests use genotyping chips that read less than 0.1% of your genome — a tiny pre-selected set of common variants. They are optimized for ancestry and population-level traits, not clinical genetic findings. The Dante Genome Test sequences 100% of your genome at 30X coverage, the same standard used in clinical diagnostic settings. The two tests are not comparable in scope, methodology, or clinical utility.
How long does it take to get results, and how are they delivered?
Your collection kit ships within 48 hours of ordering. Once your sample arrives at our CLIA-certified laboratory, sequencing and analysis takes 6–8 weeks. Results are delivered securely to your Genome Manager, where you can access your reports, share them with your physician, and receive automatic updates as new findings are validated against your genome.
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