PTEN-Related Disorders

Mutations in PTEN can cause many different disorders, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. They can also cause autism spectrum disorders with macrocephaly, congenital malformations, and/or increased risks for cancer. 


Mutations in PTEN can cause many different disorders, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. They can also cause autism spectrum disorders with macrocephaly, congenital malformations, and/or increased risks for cancer. 

Disease Name 
PTEN-related disorders
Cowden syndrome
PTEN hamartoma tumor syndrome (PHTS)
Bannayan-Riley-Ruvalcaba syndrome
Proteus syndrome
Autism spectrum disorder with macrocephaly
Disease Information 

Mutations in PTEN cause PTEN hamartoma tumor syndrome (PHTS), an umbrella term including the following autosomal dominant syndromes:1,2

  • Bannayan-Riley-Ruvalcaba syndrome (BRRS): a rare congenital disorder characterized by macrocephaly, developmental delay, learning disability, hamartomatous intestinal polyposis, and pigmented penile macules.
  • Cowden syndrome (CS): a multiple hamartoma syndrome associated with a high risk of developing benign and malignant tumors of the thyroid, breast, and endometrium. Research suggests there are increased risks for kidney cancer, colorectal cancer, and melanoma, however these risks have not yet been well defined.
  • PTEN-related Proteus syndrome (PS): a complex, highly variable disorder frequently following mosaic distribution involving congenital malformations and a distinct facial appearance. PS is characterized by over growth of limbs, skull, vertebrae and external auditory meatus.5
  • Proteus-like syndrome:  describes individuals who appear to have PS but do not meet full clinical requirements for diagnosis.6 Some individuals with an autism spectrum disorder and macrocephaly (greater than 2 standard deviations above the mean) have been found to harbor mutations in PTEN.

In addition to a wide spectrum of non-malignant clinical features including mucocutaneous lesions/abnormalities, thyroid abnormalities, fibrocystic disease, multiple uterine leiomyoma, intestinal polyposis, and macrocephaly, PHTS is also characterized by numerous malignant tumors. Pathogenic PTEN mutations have historically been estimated to confer a 25-50% lifetime risk of female breast cancer, a 10% lifetime risk of thyroid cancer, and a 5-10% risk of endometrial cancer.1

However, data from a large study of PTEN mutation carriers suggests much  higher lifetime cancer risks (up to 85% for female breast cancer, 35% for thyroid cancer, 28% for endometrial cancer) in individuals with PHTS, as well as significantly increased lifetime risks of renal (34%) and colorectal (9%) cancers and melanoma (6%) compared to the general population.10 These same data suggest that there is some genotype/phenotype correlation; PTEN promoter mutations are correlated with the highest female breast cancer risks, while nonsense mutations are correlated with the highest colorectal cancer risks.10 The risk of breast cancer for male PTEN carriers may also be increased compared to the general population, but these exact risks have yet to be determined.11 

Testing Benefits & Indication 

Genetic testing is useful for:

  • Diagnostic confirmation in symptomatic individuals
  • Guiding screening recommendations and risk-reducing options for PTEN mutation positive patients and their relatives
  • Testing of at-risk asymptomatic family members (including prenatal diagnosis)
  • Molecular confirmation of a diagnosis to avoid unnecessary testing and procedures

Indications for PTEN genetic testing vary significantly based on clinical presentation.  Major and minor criteria have been established based on the features of PHTS and are used for testing and clinical diagnostic criteria.14 Individuals with the following combinations of features may be appropriate candidates for PTEN genetic testing: 

  • 2 or more major criteria, with one being macrocephaly
  • 3 major criteria without macrocephaly
  • 1 major and ≥ 3 minor criteria
  • ≥ 4 minor criteria  
Major Critera
Minor Criteria
  • Breast cancer
  • Endometrial carcinoma
  • Epithelial thyroid cancer (follicular)
  • Multiple GI hamartomas or ganglioneuromas
  • Macrocephaly (occipital frontal circumference ≥97th percentile)
  • Macular pigmentation of glans penis
  • Mucocutaneous lesions
    • Biopsy proven trichilemmoma
    • Multiple palmoplantar keratosis
    • Multiple or extensive oral mucosal papillomatosis
    • Multiple cutaneous papules
  • Colorectal cancer
  • Epithelial thyroid cancer (papillary or follicular variant)
  • Genitourinary tumors (especially renal cell carcinoma)
  • An autism spectrum disorder
  • Other thyroid lesions (e.g. adenoma, multinodular goiter)
  • Intellectual disability (IQ ≤ 75)
  • Single GI hamartomas or ganglioneuromas
  • Lipomas
  • Testicular lipomatosis
  • ≥3 esophageal glycogenic acanthoses
  • Vascular anomalies


The American College of Medical Genetics and Genomics recommends PTEN testing for any child with an autism spectrum disorder and macrocephaly.9

PTEN testing is also recommended for individuals with:

  • A personal history of BRRS 
  • ≥ 2 biopsy proven trichilemmomas
  • Features that meet clinical diagnostic criteria for CS/PHTS
  • Family history of a known PTEN mutation
  • Lhermitte-Duclos disease, even in the absence of other signs of PHTS
Test Description 

PTEN coding exons1-9 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. In addition, sequencing of the promoter region (c.-1300 to c.-745) is performed. Gross deletion/duplication analysis determines gene copy number for coding exons 1-9. 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.15 Gross deletion/duplication analysis of PTEN 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).

Mutation Detection Rate 

PTEN mutations can be found in ~85% of individuals with CS, 65% of individuals with BRRS, and 20% of individuals with PS. Furthermore, gross deletions have been found in 10% of individual with BRRS and/or CS-like syndrome (clinical sensitivity).

In the setting of an autism spectrum disorder, PTEN mutations have been reported in~5% of patients who also have macrocephaly, and another 12% of patients diagnosed with developmental delay or intellectual disability (clinical sensitivity).9

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

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Prenatal testing is available. 

Turnaround Time 
2106 PTEN Sequencing and Deletion / Duplication  14-21 
2102 PTEN Specific Site Analysis 7-14 


  1. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: An overview. Genet Med. 2009;11(10):687-94.
  2. Eng C. PTEN: One Gene, Many Syndromes. Hum Mutat. 2003;22(3):183-98. doi: 10.1002/humu.10257.
  3. Gorlin RJ, Cohen MM, Condon LM, Burke BA. Bannayan‐Riley‐Ruvalcaba syndrome. Am J Med Genet. 1992;44(3):307-14.
  4. Nelen MR, van Staveren WCG, Peeters EAJ, Hassel MB, Gorlin RJ, Hamm H, et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997;6(8):1383-7.
  5. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006;14(11):1151-7.
  6. Waite KA, Eng C. Protean PTEN: Form and Function. Am J Hum Genet. 2002;70(4):829-44. doi:
  7. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42(4):318-21.
  8. McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Research. 2010;3(3):137-41.
  9. Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough? Genet Med. 2007;9(5):268-74.
  10. Tan M-H, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime Cancer Risks in Individuals with Germline PTEN Mutations. Clinical Cancer Research. 2012;18(2):400-7. doi: 10.1158/1078-0432.CCR-11-2283. PubMed PMID: PMC3261579.
  11. Fackenthal JD, Marsh DJ, Richardson A-L, Cummings SA, Eng C, Robinson BG, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38(3):159-64.
  12. Zhou X-P, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am Journ Hum Genet. 2003;73(2):404-11.
  13. Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med. 2009;11(2):111-7.
  14. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN Hamartoma Tumor Syndrome; systematic review and revised diagnsotic criteria.  J Natl Cancer Inst. 2013; 105:1607-1616.
  15. 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.