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Condition report · Cancer
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.
A condition report looks for rare variants known to cause the conditions it covers.
A rare, inherited disorder characterized by multiple benign tumor-like growths (hamartomas) in various tissues, and an increased risk of developing certain cancers, particularly of the breast, thyroid, and endometrium, due to a mutation in the PTEN gene.
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.
Autosomal dominant
Any Cowden disease in which the cause of the disease is a mutation in the PTEN gene.
Genes analysed
Also known as
Cowden disease caused by mutation in PTEN; Cowden syndrome type 1; CS; CWS1; Lhermitte-Duclos syndrome; PTEN Cowden disease
Any Cowden disease in which the cause of the disease is a mutation in the SDHB gene.
Also known as
Cowden disease caused by mutation in SDHB; Cowden syndrome type 2; CWS2; SDHB Cowden disease
Any Cowden disease in which the cause of the disease is a mutation in the SDHD gene.
Also known as
Cowden disease caused by mutation in SDHD; Cowden syndrome type 3; CWS3; SDHD Cowden disease
Any Cowden disease in which the cause of the disease is a mutation in the KLLN gene.
Also known as
Cowden disease caused by mutation in KLLN; Cowden syndrome type 4; CWS4; KLLN Cowden disease
Autosomal dominant
Any Cowden disease in which the cause of the disease is a mutation in the PIK3CA gene.
Also known as
Cowden disease caused by mutation in PIK3CA; Cowden syndrome type 5; CWS5; PIK3CA Cowden disease
Autosomal dominant
Any Cowden disease in which the cause of the disease is a mutation in the AKT1 gene.
Also known as
AKT1 Cowden disease; Cowden disease caused by mutation in AKT1; Cowden syndrome type 6; CWS6
Autosomal dominant
Any Cowden disease in which the cause of the disease is a mutation in the SEC23B gene.
Also known as
Cowden disease caused by mutation in SEC23B; Cowden syndrome type 7; CWS7; SEC23B Cowden disease
Autosomal dominant
The spectrum of PTEN-related conditions, including Cowden and Bannayan-Riley-Ruvalcaba syndromes, with hamartomas and raised risks of breast, thyroid, endometrial, kidney and other cancers.
What a diagnosis changes
Regular breast, thyroid, endometrial, kidney, bowel and skin surveillance, and testing of relatives.
Also known as
PHTS; PTEN-related Hamartoma tumor syndrome
Autosomal dominant
A benign overgrowth of the cerebellum (dysplastic gangliocytoma) that in adults is strongly associated with PTEN variants.
What a diagnosis changes
Its finding prompts PTEN testing and cancer surveillance for PTEN hamartoma tumour syndrome.
Genes analysed
Also known as
dysplastic cerebellar gangliocytoma; dysplastic gangliocytoma of cerebellum; dysplastic gangliocytoma of the cerebellum; LDD
Autosomal dominant
PTEN variants presenting with a large head size and autism spectrum disorder or developmental delay.
What a diagnosis changes
Children and adults with a PTEN variant need the same cancer surveillance as in Cowden syndrome.
Genes analysed
Also known as
macrocephaly-intellectual disability-autism syndrome
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.
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.
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.
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