• Test code: 01704
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae PTEN-Related Disorders Test

Test description

This test analyzes the PTEN gene, which is associated with PTEN hamartoma tumor syndrome (PHTS) as well as PTEN-related autism spectrum disorder.

PTEN hamartoma tumor syndrome (PHTS) includes the clinical subtypes of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome. Characteristics of these syndromes include hamartomas, macrocephaly, intellectual disability, and cancers of the breast, thyroid, and uterus. In addition, pathogenic variants in PTEN are associated with autism spectrum disorder and have been observed in individuals without any PHTS phenotype.

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

PTEN: Deletion/duplication analysis covers the promoter region.

Order test

Primary panel (1 gene)

Alternative tests to consider

PTEN can also be ordered as part of a larger panel to test for different types of hereditary cancer conditions. Depending on the individual’s clinical and family history, one of these larger panels may be appropriate. Any of these larger panels can be ordered at no additional charge.

  • PTEN hamartoma tumor syndrome
    • Cowden syndrome
    • Cowden-like syndrome
    • Bannayan-Riley-Ruvalcaba syndrome
    • PTEN-related Proteus syndrome
    • Proteus-like syndrome
  • PTEN-related autism spectrum disorder

PTEN hamartoma tumor syndrome (PHTS) encompasses four, clinically distinct, allelic disorders characterized by the formation of hamartomatous tumors. Hamartomas are caused by unregulated cellular proliferation, leading to a high risk of benign and malignant tumors requiring cancer surveillance of the thyroid, skin, breast, endometrium, kidney and colon. Individuals with Cowden syndrome have a lifetime risk of developing breast cancer up to 85% with 50% penetrance by age 50. Approximate lifetime risks for other cancers include 35% risk of thyroid cancer (typically follicular), 28% risk of endometrial cancer, 9% risk of colorectal cancer, and 35% risk of renal cell carcinoma.

Bannayan-Riley-Ruvalcaba syndrome confers similar cancer risks as Cowden syndrome; however, BRRS is a congenital disorder characterized by macrocephaly and lipomas.

PTEN-related Proteus/Proteus-like syndromes are overgrowth syndromes characterized by childhood onset progressive overgrowth of the skin, skeleton, central nervous system and adipose tissues.

In addition, pathogenic variants in PTEN have been associated with autism spectrum disorder, with and without macrocephaly, in the absence of a family history of PHTS. 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.

More than 90% of individuals with Cowden syndrome will manifest clinical features by their late twenties. By age 30, 99% will develop characteristic skin and mucous membrane findings. However, affected individuals can present with varying clinical features, even among members of the same family. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.

Individuals with PTEN mutations have an increased risk of developing the following cancers:

  • female breast cancer, 81%-85%
  • uterine cancer, 28%
  • thyroid cancer, 35%
  • kidney cancer, 35%
  • colon cancer, 9%
  • melanoma, 6%

Breast cancer in men with germline PTEN mutations has been reported, but the exact risk is unknown. Central nervous syndrome cancers have been reported, but are thought to be rare.

The clinical sensitivity of this test is dependent on the patient’s clinical presentation. For each clinical subtype, the chart below shows the percentage of clinical cases in which a pathogenic variant is expected to be identified through analysis of the PTEN gene.

Clinical subtype % of clinical cases with a pathogenic variant in PTEN
Cowden syndrome (CS) 85%
Bannayan-Riley-Ruvalcaba syndrome (BRRS) 70%
PTEN-related Proteus/Proteus-Like Syndrome 20-50%
PTEN-related macrocephalic autism spectrum disorder 10%

PHTS and PTEN-related autism spectrum disorder are inherited in an autosomal dominant pattern.

The prevalence of PHTS is currently unknown.

PTEN analysis may be considered in individuals with:

  • adult Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma)
  • characteristic mucocutaneous lesions (facial trichilemmomas, acral keratoses, and papillomatous and mucosal lesions)
  • breast cancer
  • thyroid cancer
  • endometrial cancer
  • macrocephaly
  • endometrial carcinoma
  • renal cell carcinoma
  • intellectual disability
  • autism spectrum disorder
  • fibrocystic breasts
  • uterine fibroids
  • hamartomatous intestinal polyps
  • thyroid lesions (adenomas and multinodular goiter)
  • lipomas
  • fibromas

Clinical diagnostic criteria have been established:

Testing may also be considered for those who do not meet the strict clinical diagnostic criteria for Cowden but have a strong clinical suspicion of having the condition.

  1. Ni, Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 2008; 83(2):261-8. PMID: 18678321
  2. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  3. Yu, W, et al. Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation. Hum. Mol. Genet. 2015; 24(1):142-53. PMID: 25149476
  4. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian Version 3.2019. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2019
  5. Cleveland Clinic, Genomic Medicine Institute Risk Calculator for Estimating a Patient's Risk for PTEN Mutation. http://www.lerner.ccf.org/gmi/ccscore/ Accessed June 2015.
  6. National Library of Medicine, Genetics Home Reference: Cowden Syndrome. http://ghr.nlm.nih.gov/condition/cowden-syndrome Accessed June 2015.
  7. Frazier, TW, et al. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol. Psychiatry. 2015; 20(9):1132-8. PMID: 25288137
  8. Tan, MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012; 18(2):400-7. doi: 10.1158/1078-0432.CCR-11-2283. PMID: 22252256
  9. Eng, C. PTEN Hamartoma Tumor Syndrome (PHTS). 2001 Nov 29. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488/ PMID: 20301661
  10. Orloff, MS, et al. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 2013; 92(1):76-80. PMID: 23246288

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. Sequencing analysis for exons 8 includes only cds +/- 10 bp.