• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit



10q23del; 10q23del, BZS, CWS1, DEC, GLM2, MHAM, MMAC1, PTEN1, TEP1; BZS; CWS1; DEC; GLM2; MHAM; MMAC1; PTEN1; TEP1

Associated disorders

The PTEN gene is associated with autosomal dominant PTEN hamartoma tumor syndrome (PHTS) including the clinical subtypes of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and PTEN-related autism spectrum disorder (MedGen UID: 368366). Other PTEN-associated conditions have been described (PMID: 11755638, 17392703, 27890237).

PTEN is a tumor suppressor gene that has roles in controlling cellular migration, adhesion, and angiogenesis. The PTEN gene encodes a phosphatase that negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate and the AKT/PKB signaling pathway. These functions help prevent uncontrolled cell growth that can lead to the formation of tumors.

PTEN heterozygote
MedGen UID: 368366

Clinical condition
The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of highly variable conditions with overlapping features. This spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and PTEN-related autism spectrum disorder (PMID: 20301661, 26827793, 12938083). The term PHTS was coined to describe any individual with a germline pathogenic PTEN variant, regardless of clinical presentation (PMID: 25132236).

PHTS is a multisystemic disorder primarily characterized by noncancerous tumor-like growths called hamartomas that can develop throughout the body, as well as increased risk of primarily adult-onset cancers (PMID: 26564076). Cancers most commonly associated with PHTS syndrome include breast, thyroid, and uterine cancers; there is also an increased risk of kidney, colorectal, melanoma, and central nervous system cancer. Reported cancer-specific risks in PHTS include (PMID: 22252256, 20565722, 23335809, 26564076, 26827793, 25132236):

  • female breast cancer, 67-85%
  • thyroid cancer, (typically follicular), 34-38%
  • kidney cancer, (typically papillary renal cell or chromophobe), 34-35%
  • endometrial cancer, 28%
  • colon cancer, 9%
  • melanoma, 6%
  • central nervous syndrome cancers reported, but are thought to be rare
  • male breast cancer reported, but specific risks are unknown

Reported cancer risks are primarily based on retrospective analyses of patient cohorts that extrapolates lifetime risks (PMID: 22723373, 22252256).

Affected women have an increased risk of both primary and secondary breast cancer (PMID: 25132236). Among those who have already had one breast cancer diagnosis, the risk for another primary breast cancer within the next 10 years is 29% (PMID: 24778394). Among PTEN-associated cancers, thyroid cancer presents the earliest with cases reported in childhood (PMID: 25132236).

Lhermitte-Duclos disease (LDD) and specific mucocutaneous lesions are pathognomonic findings of PHTS. LDD is a rare, benign brain tumor defined as a cerebellar dysplastic gangliocytoma (PMID: 26564076). The mucocutaneous lesions include facial trichilemmomas, mucosal papillomatous papules, and acral and plantar keratoses (PMID: 20301661, 26827793). A trichilemmoma is a hamartomatous proliferation arising from the cells of a hair follicle, most often observed on the face and neck. Mucosal papillomas typically present along the tongue, gums, or nasal epithelia (PMID: 26564076). On gross examination, the acral and palmoplantar keratoses appear as small, verrucous hyperkeratotic papules similar to viral warts or small keratoses with a central depression (PMID: 26564076).

Thyroid pathology includes multinodular goiter, adenomatous nodules, follicular adenomas and Hashimoto’s thyroiditis (PMID: 26564076, 23934601, 21659347, 25132236, 6863628). Gastrointestinal polyps are present in most adults with PHTS (PMID: 26564076). Polyp types include hamartomas, hyperplastic polyps, ganglioneuromas, and adenomas (PMID: 26564076, 20301661).

Other characteristic features of PHTS include macrocephaly and dolichocephaly (PMID: 26564076). The macrocephaly in PHTS is due to overgrowth of brain tissues as opposed to hydrocephalus (PMID: 26564076). Approximately 94% of people with PHTS have head circumferences greater than two standard deviations for age and sex (PMID: 26564076).

Pathogenic variants in PTEN are associated with developmental delay, intellectual disability, and autism spectrum disorder, with and without macrocephaly (PMID: 26564076, 19265751, 25288137). The range of developmental impact varies widely, ranging from absent cognitive issues and normal-to-superior IQ, to severe autism spectrum disorder with or without intellectual disability (PMID: 26564076). More frequent white matter abnormalities and more significant cognitive delays have been reported in individuals with PTEN-related autism spectrum disorder versus non-PTEN-related autism spectrum disorder (PMID: 19265751, 25288137).

More than 90% of affected individuals will display clinical findings by the third decade of life (PMID: 20301661). While symptoms can present at any age, many affected children are first ascertained for macrocephaly, neurodevelopmental delays, and/or benign skin lesions such as lipomas or penile freckling; however, the mucocutaneous features may go unrecognized (PMID: 26564076).

Additional clinical findings described in PHTS include various benign tumors such as fibrocystic breast disease (PMID: 23335809, 25132236, 9445133, 3698331), uterine fibroids (PMID: 23335809, 3698331), ovarian cysts (PMID: 23335809, 6863628) and cerebrovascular malformations (PMID: 23335809, 25132236, 17526801). However, because fibrocystic breasts and uterine fibroids are common in the general population, it is uncertain if these are significant in their association with PHTS (PMID: 21659347).

Clinical diagnostic criteria for PHTS
Clinical diagnostic criteria for PHTS have been established (PMID: 24136893). A clinical diagnosis can be established for those with either of the following:

  1. Three or more major criteria, but one must be macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas; or
  2. Two major and three minor criteria

Major criteria

  • Breast cancer
  • Endometrial cancer (epithelial)
  • Thyroid cancer (follicular)
  • Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3)
  • Lhermitte-Duclos disease (adult)
  • Macrocephaly (≥97 percentile: 58cm for females, 60cm for males)
  • Macular pigmentation of the glans penis
  • Multiple mucocutaneous lesions (any of the following):
    • Multiple trichilemmomas (≥3, at least one biopsy proven)
    • Acral keratoses (≥3 palmoplantar keratotic pits and/or acral
    • hyperkeratotic papules)
    • Mucocutaneous neuromas (≥3)
    • Oral papillomas (particularly on tongue and gingiva), multiple (≥3)
    • OR biopsy proven OR dermatologist diagnosed

Minor criteria

  • Autism spectrum disorder
  • Colon cancer
  • Esophageal glycogenic acanthosis (≥3)
  • Lipomas (≥ 3)
  • Mental retardation (i.e., IQ ≤ 75)
  • Renal cell carcinoma
  • Testicular lipomatosis
  • Thyroid cancer (papillary or follicular variant of papillary)
  • Thyroid structural lesions (e.g., adenoma, multinodular goiter)
  • Vascular anomalies (including multiple intracranial developmental venous anomalies)

Atypical PTEN-Associated Subtypes
PHTS has a phenotypic subtype that manifests with asymmetric overgrowth, macrocephaly, cutaneous vascular malformations, and tumor susceptibility. While the full spectrum of this subtype is unclear, it has been reported to occur as the consequence of a germline pathogenic variant in PTEN in addition to a somatic, mosaic second deleterious PTEN variant contributing to the segmental attributes (PMID: 11476841, 11755638, 27890237, 17388921, 17392703). This subtype has also been described as type II segmental Cowden syndrome (PMID: 17388921) and SOLAMEN syndrome (PMID: 17392703) in the literature.

Gene information
PTEN is a tumor-suppressor gene that antagonizes the PI3K-AKT/PKB signaling pathway and modulates cell cycle progression and cell survival (UniProtKB – P60484 (PTEN_HUMAN); http://www.uniprot.org/uniprot/P60484. Accessed February 2017). Evidence suggests that PTEN plays a role in cell migration, adhesion, and angiogenesis (NCBI. PTEN gene. https://ghr.nlm.nih.gov/gene/PTEN. Accessed February 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

Pathogenic variants in the PTEN gene have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to his/her offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but up to 44% occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 25132236). This means that the individual did not inherit the pathogenic variant from either parent, but now has a 50% risk of passing it on to future offspring.

Medical management guidelines for individuals with PHTS have been established by the National Comprehensive Cancer Network (NCCN) (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018, Accessed February 2018):

Management recommendations for women include:

  • Breast awareness beginning at 18 (can include breast self exam)
    • Periodic, consistent breast self-examination may facilitate breast self-awareness
  • Annual or semiannual clinical breast exams beginning either at 25 years of age, or 5–10 years before the earliest known age of breast cancer onset in the family
  • Annual mammography and breast MRI either beginning at 30–35 years of age, or 5–10 years before the earliest age of onset in the family
  • For women over 75 years of age, management should be considered on an individual basis
  • For women treated for breast cancer, screening of the remaining breast tissue with annual mammography and breast MRI should continue
  • For endometrial cancer screening, encourage education and prompt response to symptoms such as abnormal bleeding and consider of annual endometrial biopsy and/or ultrasound beginning at age 30–35 years of age
  • Discuss option of hysterectomy after childbearing is complete and counsel regarding the degree of protection such a procedure provides, extent of endometrial cancer risk, reproductive desires, and the psychosocial and quality of life aspects of such a procedure
    • Note that oophorectomy for CS/PHTS is not indicated, however may be indicated for other reasons
  • Counsel regarding the option of risk-reducing mastectomy with consideration of the degree of protection such a procedure provides, extent of breast cancer risk, reconstruction options, and the psychosocial and quality of life aspects of such a procedure

Management recommendations for both men and women include:

  • Annual comprehensive physical exams beginning at age 18, or five years prior to the earliest known age of cancer diagnosis in the family, with particular attention to the thyroid
  • Annual thyroid ultrasound examination beginning at the time of CS/PHTS diagnosis
  • Colonoscopies every 5 years, starting at age 35, unless symptomatic
    • If there is a close relative with colon cancer diagnosed before age 40, begin colonoscopies 5-10 years before the earliest known colon cancer diagnosis in the family
    • Intervals for screening should be reduced if symptoms or polyps are identified
  • Consider renal ultrasound starting at age 40, and every 1-2 years thereafter
  • Dermatological management may be indicated in some affected individuals
  • Consider a baseline psychomotor assessment in childhood at the time of diagnosis
    • If symptomatic, consider brain MRI
  • Education regarding the signs and symptoms of cancer

Other considerations:

  • Referral for genetic counseling, inclusive of a discussion regarding recurrence risks
  • Advise affected individuals of reproductive age regarding prenatal diagnosis and assisted reproduction options
  • Encourage affected individuals to inform relatives about possible inherited cancer risks, options for risk assessment and management
  • Genetic counseling and testing is recommended for at-risk relatives

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a pathogenic PTEN variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant PTEN data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Additional reference
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed February, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Review date: February 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
PTEN* NM_000314.4

*PTEN: Deletion/duplication analysis covers the promoter region.