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.

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Primary panel (1 gene)


PTEN: Deletion/duplication analysis covers the promoter region.

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. Cleveland Clinic, Genomic Medicine Institute Risk Calculator for Estimating a Patient's Risk for PTEN Mutation. Accessed June 2015.
  2. Eng, C. PTEN Hamartoma Tumor Syndrome (PHTS). 2001 Nov 29. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301661
  3. 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
  4. 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
  5. National Comprehensive Cancer Network, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian. Accessed September 2015.
  6. National Library of Medicine, Genetics Home Reference: Cowden Syndrome. Accessed June 2015.
  7. 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
  8. 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
  9. 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
  10. 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

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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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

PTEN: Deletion/duplication analysis covers the promoter region.