Cowden Syndrome — PTEN loss-of-function producing one of the highest lifetime breast cancer risks of any hereditary syndrome, alongside elevated endometrial, thyroid, colorectal, and kidney cancer risk.
PTEN is on the ACMG SF v3.2 list of genes requiring secondary findings reporting in clinical genome sequencing. Whole genome sequencing characterizes the complete PTEN locus — including promoter region variants and large deletions that standard cancer panels routinely miss.
Cowden Syndrome — PTEN Hamartoma Tumor Syndrome
Cowden syndrome (CS) — the most common of the PTEN hamartoma tumor syndromes (PHTS) — is an autosomal dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in PTEN (phosphatase and tensin homolog) on chromosome 10q23.31. PTEN is a tumor suppressor that regulates the PI3K/AKT/mTOR signaling pathway; loss of PTEN function leads to unchecked cellular proliferation and tumor formation. Cowden syndrome is characterized by mucocutaneous lesions (trichilemmomas, papillomatous papules, and acral keratoses), macrocephaly, benign hamartomas in multiple organs, and substantially elevated risks for multiple malignancies. The estimated prevalence is 1 in 200,000, though molecular diagnoses reveal significantly higher frequency.
Lifetime cancer risks in PTEN pathogenic variant carriers are among the highest documented for any hereditary cancer gene: breast cancer risk reaches 67-85% (compared to ~12% population average); endometrial cancer risk approaches 28-44%; thyroid cancer risk (predominantly follicular) reaches 21-38%; colorectal cancer risk is elevated (9-18%); and renal cell carcinoma risk is approximately 34%. Male carriers have elevated breast cancer risk and are also at elevated risk for thyroid and colorectal cancers. Bannayan-Riley-Ruvalcaba syndrome (BRR) and Proteus syndrome (PS) represent allelic PTEN disorders with overlapping but distinct clinical features, all caused by PTEN pathogenic variants.
Approximately 25% of individuals meeting clinical diagnostic criteria for Cowden syndrome do not have an identifiable PTEN coding sequence variant — this group may harbor PTEN promoter region variants, deep intronic variants, large genomic rearrangements, or pathogenic variants in other PHTS-associated genes (SDHB, SDHD, KLLN). NCCN guidelines recommend comprehensive PTEN analysis including deletion/duplication testing as part of complete PHTS evaluation. Management of confirmed PTEN carriers includes annual breast MRI beginning at age 30, annual mammograms beginning at age 30-35, consideration of risk-reducing mastectomy, annual endometrial sampling beginning at age 30-35, and annual thyroid ultrasound.
PTEN hamartoma tumor syndromes include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome — allelic conditions with overlapping but clinically distinguishable presentations, all caused by PTEN pathogenic variants.
PTEN promoter variants and large genomic rearrangements account for up to 25% of PHTS cases — variants that standard hereditary cancer panels, which sequence only PTEN coding exons, systematically miss.
PTEN promoter region variants are excluded from most cancer panel designs
Germline pathogenic variants in the PTEN promoter region — particularly a recurrent c.-1019_-1018dupTA variant — have been identified in Cowden syndrome patients who test negative on standard PTEN exon-sequencing panels. These variants reduce PTEN transcription, producing functional haploinsufficiency without altering the coding sequence. Standard cancer panels sequence only the 9 PTEN coding exons and canonical splice sites; they do not include the promoter region or intergenic regulatory elements. Whole genome sequencing reads the complete PTEN locus including the promoter, all introns, and the 3' UTR — the regions where regulatory pathogenic variants reside.
Multi-cancer risk management requires confirmed PTEN status at the earliest possible age
PTEN-related cancer risks are among the highest of any hereditary syndrome, and surveillance must begin in the third decade of life — before most breast and endometrial cancers in this population are clinically detectable. NCCN recommends annual breast MRI and mammography from age 30, with endometrial surveillance beginning at 30-35. This aggressive surveillance schedule is justified by the lifetime risk data but requires a confirmed PTEN pathogenic variant to implement. A negative result on an incomplete panel — one that did not evaluate the PTEN promoter or structural rearrangements — may be providing false reassurance that delays necessary surveillance by years.
Your full DNA (not just a part of it)
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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Forty years of uncertainty. One test.
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.
Sequenced in 2019. The data worked in 2021.
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.
It runs in your family. Now you can know if it runs in your genes.
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.
Learn more →Your diagnosis may be right. Your treatment plan may be incomplete.
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.
Learn more →You want to know before something forces the question.
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.
Learn more →You already took a DNA test. Here's what it couldn't tell you.
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Dante Genome Test helped specialists at a UK national acute hospital in the identification of Noonan Syndrome and a rare leukemia-associated genetic variant that had gone undetected. That result changed the medical care of the patient.
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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.
We work with patient advocacy groups worldwide.
Dante Labs works with patient advocacy groups of any size — for Cowden Syndrome — PTEN Hamartoma Tumor Syndrome and other conditions, rare and common. We support groups in any country, including virtual patient advocacy groups.
We can provide customized reports, group discounts, and packages tailored for your members. Please reach out using the form and we'll be in touch within two business days.
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Ships within 48 hours · Results in 6–8 weeks
