Description 
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndromes (PHTS) are primarily characterized by hamartomatous tumors (disorganized growths of native cells in native tissues) caused by PTEN germline mutations. PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (PLS).^1,2

Genetic counseling is strongly recommended for individuals pursuing genetic testing for PHTS. 

Terms such as male and female are used when necessary to refer to sex assigned at birth.

Policy
All major and minor criteria are defined in Note 1.

1. For asymptomatic individuals who are in a family with a known pathogenic PTEN mutation, the following testing is considered MEDICALLY NECESSARY:
   1. Testing restricted to the known familial mutation.
   2. Comprehensive PTEN gene sequencing when the specific PTEN mutation is unknown.
2. For individuals suspected of having Cowden Syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS), genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY when at least one of the following clinical signs is present:
   1. Three or more major criteria (one must be macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas).
   2. Two major and three minor criteria.
3. For individuals not meeting the clinical diagnostic criteria above, genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY when the individual has a personal history of any one of the following:
   1. Adult Lhermitte-Duclos disease (cerebellar tumors).
   2. Autism spectrum disorder and macrocephaly.
   3. Two or more biopsy-proven trichilemmomas.
   4. Two or more major criteria (one must be macrocephaly).
   5. Three major criteria without macrocephaly.
   6. Two major and two or more minor criteria (for individuals without macrocephaly).
   7. One major and three or more minor criteria .
   8. Four or more minor criteria .
4. For individuals with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS), genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY.
5. For at-risk individuals with a relative who has been clinically but not genetically diagnosed with CS/PHTS or BRRS, genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY when at least one of the following conditions are met:
   1. The at-risk individual has any one major criterion.
   2. The at-risk individuals has two minor criteria .
6. For individuals with a PTEN pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline analysis, genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

7. For all other situations not described above, genetic testing for a PTEN mutation is considered NOT MEDICALLY NECESSARY.

NOTES:

Note 1: The NCCN provides the following major and minor testing criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome (Category 2A recommendation: based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate):³

Major Testing Criteria

• Breast cancer
• Endometrial cancer (epithelial)
• Follicular thyroid cancer
• Three or more GI hamartomas or ganglioneuromas
• Lhermitte-Duclos disease (adult)
• Macrocephaly (megalocephaly) (ie, ≥97%, 58 cm in adult female, 60 cm in adult male)
• Macular pigmentation of glans penis
• Mucocutaneous lesions (any of the following):
  • Trichilemmoma (three or more, at least one biopsy-proven)
  • Three or more palmoplantar keratotic pits and/or acral hyperkeratotic papules
  • Three or more mucocutaneous neuromas
  • Oral papillomas, particularly on tongue and gingiva (three or more papillomas or one biopsy-proven or dermatologist diagnosed papilloma)

Minor Testing Criteria

• Autism spectrum disorder
• Colon cancer
• Three or more esophageal glycogenic acanthoses
• Three or more lipomas
• Intellectual disability (i.e., IQ ≤75)
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid structural lesions (e.g., adenoma, nodule[s], goiter)
• Renal cell carcinoma
• Single GI hamartoma or ganglioneuroma
• Testicular lipomatosis
• Vascular anomalies (including multiple intracranial developmental venous anomalies)

Table of Terminology   

Term	Definition
ACG	American College of Gastroenterology
aCGH	Array comparative genomic hybridization
ACMG	American College of Medical Genetics and Genomics
AKT	Protein Kinase B
ALK	Anaplastic lymphoma kinase gene
ASDs	Autism spectrum disorders
BEN	Benign
BP	Base pair
BRCA1	Breast cancer type 1 gene
BRCA2	Breast cancer type 2 gene
BRRS	Bannayan-Riley-Ruvalcaba syndrome
CC	Cleveland Clinic
CC15	Cleveland Clinic Score of 15
CGH	Comparative genomic hybridization
CLIA ’88	Clinical Laboratory Improvement Amendments of 1988
CMS	Centers for Medicare and Medicaid Services
CONF	Conflicting
CS	Cowden Syndrome
DNA	Deoxyribonucleic acid
DTC	Differentiated thyroid carcinoma
ERCC2	ERCC excision repair 2 gene
FDA	Food and Drug Administration
FTC	Follicular thyroid carcinoma
GI	Gastrointestinal
HRAS	HRas proto-oncogene
IQ	Intelligence quotient
LBEN	Likely benign
LDD	Lhermitte-Duclos disease
LDT	Laboratory-developed test
LPATH	Likely pathogenic
MLPA	Multiplex ligation-dependent probe amplification
mTOR	Mechanistic Target of Rapamycin
MUTYH	mutY DNA glycosylase
NCCN	National Comprehensive Cancer Network
NGS	Next generation sequencing
NORD	National Organization for Rare Disorders
PATH	Pathogenic
PCR	Polymerase chain reaction
PHTS	PTEN Hamartoma Tumor Syndromes
PI3K	Phosphatidylinositol 3-Kinase
PLS	Proteus-Like Syndrome
PS	Proteus Syndrome
PTEN	Phosphatase and tensin homolog
qPCR	Quantitative polymerase chain Reaction
RET	Ret proto-oncogene
RNA	Ribonucleic acid
SOLAMEN	Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation, and Epidermal Nevus
TSC2	Tuberous sclerosis complex 2 gene
VUS	Variant of uncertain significance

Rationale 
Tumor suppressor genes serve several purposes within the body; these genes are able to regulate cell division, restore DNA errors, and tell cells when to die (a process known as apoptosis). Communication of these processes occurs via various cell signaling pathways. In particular, the tumor suppressor gene known as phosphatase and tensin homolog (PTEN) is an important phosphatase regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and the mechanistic target of rapamycin (mTOR) signaling pathway.^2,4 The PI3K/AKT and mTOR signaling pathways are critical for cell proliferation, cell cycle progression, and apoptosis.

Loss of function of the PTEN gene contributes to an increased risk of both benign and malignant tumors and is implicated in increased lifetime risks of breast, thyroid, uterine, renal, and other cancers; patients may also display clinical features such as cognitive changes, skin changes, macrocephaly (enlarged head) and intestinal polyposis.⁵ Dental malformations have also been identified in 27% of pediatric PHTS patients.⁶ Further, loss of PTEN gene functionality results in a spectrum of autosomal dominant disorders known PTEN hamartoma tumor syndromes (PHTS); this includes CS, Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related PS, and PLS.^1,7 Autism spectrum disorders (ASDs) with macrocephaly and adult Lhermitte-Duclos disease (LDD) have also been associated with PHTS.^2,8

A diagnosis of PHTS is established by identification of a germline pathogenic variant in PTEN via molecular genetic testing. A single gene sequence analysis will detect up to 85% of CS cases, 65% of BRRS cases, 50% PLS cases, and 20% of PS cases. Deletion and duplication analysis or promoter region analysis may also detect additional cases, but further research is required. In addition to single gene analysis, gene panels or further comprehensive testing may assist with clinical management.¹ All types of mutations have been reported including missense, nonsense, splice site, insertions, and deletions; therefore, PTEN mutation testing usually requires sequence analysis of the entire coding region and deletion/duplication analysis.^1,9 Mutations have also been reported in the PTEN promoter, and a test for mutations in this region of the gene has become clinically available.² Mingo, et al. (2018) recently found that the pathogenicity of frequent PTEN mutations targeting the N-terminus “may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway.” Germline PTEN mutations are found in approximately 20 to 34% of individuals who meet clinical criteria for CS or who meet criteria for genetic testing.^8,11,12 This number seems to be highly variable as Giorgianni, et al. (2013) state that approximately 80% of CS patients have a PTEN mutation at locus 10q23.2. Recently genotype-phenotype correlations identified that 72% of PTEN mutations are located in the tensin-type C2 domain.⁶

Cowden Syndrome (CS)
Cowden Syndrome is defined by multiple hamartomas with a high risk for benign and malignant tumors in the thyroid, breast, and endometrium. Besides multiple hamartomas in a variety of tissues, patients typically exhibit macrocephaly as well as characteristic dermatologic manifestations, such as trichilemmomas (benign tumors originating from hair follicles) and papillomatous papules (wart-like growths).¹⁴ For individuals with CS, the lifetime risk of developing breast cancer is as high as 85%; for thyroid cancer, which is usually follicular carcinoma, the lifetime risk is as high as 35%; finally, for endometrial cancer, the risk may reach as high as 28%.^1,7 The estimated prevalence of CS is 1 in 200,000 to 250,000, though it is likely underreported.² Of all PHTS, only CS has been documented to confer a predisposition to cancer; however, it has been suggested that any patients with PTEN mutations should be assumed to have cancer risks similar to CS.²

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
Bannayan-Riley-Ruvalcaba syndrome is characterized by hamartomas along with macrocephaly, lipomas, and pigmented penile macules. It is also associated with high birth weight, developmental delay or deficiency, proximal muscle myopathy, joint hypermobility, high palate, and scoliosis.² Similar mutations in the PTEN gene are found in both CS and BRRS, which are now considered phenotypically distinct presentations of a similar genetic abnormality.^9,15

PTEN-related Proteus Syndrome (PS)
PTEN-related PS is characterized by hamartomatous overgrowth of multiple tissues with hyperostosis (excessive bone growth), vascular malformations, dysregulation of fatty tissues, connective tissue nevi, and epidermal nevi. Phenotypic features of PS are usually present at birth and progress over an individual’s lifetime.¹⁶

Proteus-like Syndrome (PLS)
Proteus-like syndrome is undefined but typically refers to individuals with similar clinical features to PS who do not meet the diagnostic criteria.^1,7,16 Overall, limited information is available on PLS. Stanich and Roberts (2023) report that PLS cases typically exhibit “a distinct type of epidermal nevus (also referred to as segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus (SOLAMEN) syndrome or type 2 segmental Cowden syndrome).”²

Autism Spectrum Disorders (ASDs)
Autism Spectrum Disorders are a collection of disorders presenting with common abnormalities associated with social and communication behaviors. A few studies have been published which research the relationship between PTEN mutations and ASDs. Schaefer and Mendelsohn (2013) completed a literature review of at least seven different studies and determined that 15 of 318 (5%) individuals with an ASD diagnosis had a pathogenic PTEN mutation; further, macrocephaly was present in all 15 cases.¹⁷

Lhermitte-Duclos Disease (LDD)
Lhermitte-Duclos disease is a rare disease characteristic of benign tumor development in the granule cells of the cerebellum. It has been reported that “Most LDD patients appear to have a germline loss of the PTEN allele and go on to lose the remaining PTEN allele at some point, thereby allowing abnormal growth of the granule cells.”¹³ LDD often develops in conjunction with CS, but may also develop singularly.²

Proprietary Testing
Ambry Genetics, GeneDx, LabCorp Invitae, and Blueprint Genetics all have genetic tests for PTEN mutations. Invitae and Blueprint Genetics both use a next generation sequencing (NGS) assay that performs full PTEN gene sequencing and deletion/duplication analysis.^18-21 The Invitae assay “achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions, and deletions <15bp [base pair] in length, and exon-level deletions and duplications.” The Blueprint Genetics NGS sequencing assay for single genes performs similarly with a >99% specificity and sensitivity for single nucleotide variants, including insertions, deletions, and indels up to 50 bp. The Invitae assay has a clinical sensitivity of 85% for CS, 70% for BRRS, 20-50% for PLS, and 10% for PTEN-related macrocephalic autism spectrum disorder. The clinical sensitivity is not provided by Blueprint Genetics; however, clinical sensitivity is said to vary based on patient clinical presentation.^20,21

GeneDx utilizes a PCR-amplified assay with capillary sequencing to confirm variants of clinical or uncertain significance. Their assay also performs deletion/duplication testing using “either exon-level CGH [comparative genomic hybridization] or MLPA [multiplex ligation-dependent probe amplification]. Confirmation of copy number changes is performed by MLPA, qPCR [quantitative polymerase chain reaction], or repeat aCGH [array CGH] analysis.”¹⁹ GeneDx has found that “for those probands with Cowden syndrome, sequence analysis of the coding and promoter regions is expected to detect 47-80% of causative variants, while large deletions and duplications have been reported. For individuals with Bannayan-Riley-Ruvalcaba syndrome, ~60% of causative pathogenic variants will be detected by sequencing while 11% will be detected by deletion/duplication analysis.”¹⁹ Ambry Genetics also utilizes a PCR-amplified assay with NGS, as well as Sanger Sequencing for any regions “missing or with insufficient read depth coverage for reliable heterozygous variant detection.” Their assay also performs gross deletion and duplication analysis, with any copy number changes detected from NGS confirmed by targeted chromosomal microarray or MLPA. Their analytical sensitivity is >99.9% for described mutations in the PTEN gene when present and has an identical clinical sensitivity to that described by Invitae.¹⁸

Clinical Utility and Validity 
Yehia et al. (2018) conducted a four-year multicenter study; all participants had suspected BRRS or Cowden/Cowden-like (CS/CS-like) syndromes without PTEN mutations. Exome sequencing and targeted analysis was completed on 59 genes supported by the American College of Medical Genetics and Genomics (ACMG), as well as on 24 additional genes known to be associated with inherited cancer syndromes. “Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in seven of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS.”²²

Ngeow, et al. (2015) estimated the cost effectiveness of each PTEN mutation detected in CS-like patients using the PTEN Cleveland Clinic (CC) score. This is a risk assessment tool which helps to estimate an individual’s risk of having a PTEN mutation. Several questions are answered through an online survey, and a total risk score between 0 and 100 is provided.²⁴ The authors found that the cost to detect one PTEN mutation was between $3720 to $4573 at a CC score of 15 (CC15). The authors also concluded that “In sensitivity analyses, CC15 is robustly the most cost-effective strategy for probands who are younger than 60 years.”²³

Isik, et al. (2020) researched the genotype to phenotype correlation of patients with PTEN mutations. A total of ten molecularly confirmed PHTS patients participated in this study; these participants originated from seven different families. The authors note that “Macrocephaly was the most common clinical finding, involving all patients. This was followed by skin lesions, neurodevelopmental delay, and pathologic cranial magnetic resonance imaging findings.”²⁵ Further, sequencing of the PTEN gene identified seven different PTEN variants; four variants were located in exon five. The authors conclude by highlighting the importance of screening for PTEN mutations in patients with macrocephaly, particularly due to an increased risk of cancer.²⁵

Jonker, et al. (2020) conducted an extensive literature search to identify evidence to support a thyroid carcinoma surveillance program among children with PHTS. They found that children with PHTS were at an increased risk of developing differentiated thyroid carcinoma (DTC), “with 4 years being the youngest age reported at presentation and FTC [follicular thyroid carcinoma] being overrepresented.” This finding supports genetic testing for PTEN mutations, as that could provide guidance and awareness for potential thyroid cancer development at an early age and reduce morbidity with early diagnosis. “Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%.”²⁶ This recommendation was also supported by Baran, et al. (2021), who further retrospectively investigated patients at the Children’s Hospital of Philadelphia with a PHTS diagnosis between January 2003 and June 2019. They found “the most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%),”^26,27 which also appears to corroborate the physical findings of Isik, et al. (2020).

Cummings, et al. (2022) conducted a systematic review and meta-analysis of the behavioral and psychological features associated with PTEN mutations and the prevalence of autism spectrum disorder characteristics. Using a random effects model, the researchers estimated a pooled prevalence of ASD at 25%, with frequent reporting of intellectual disability and developmental delay, including issues that pertained globally, to motor, and to speech and language. Less frequently were mentions of emotional difficulties ad impaired cognitive functioning. This indicates that further research using appropriate comparison groups may provide greater depth of the association with aberrations affecting PTEN.²⁸

The International Cowden Consortium Operational Criteria for the Diagnosis of Cowden Syndrome Ver 2000 
The International Cowden Consortium established the operational criteria for diagnosing CS in 1995 and updated them in 2000, categorizing features into Pathognomonic, Major, and Minor criteria.

• Pathognomonic criteria include mucocutaneous lesions such as facial trichilemmomas, acral keratoses, papillomatous lesions, and mucosal lesions.
• Major criteria include significant features such as breast carcinoma, thyroid carcinoma, macrocephaly, endometrial carcinoma, and LDD.
• Minor criteria include thyroid lesions, intellectual disabilities, gastrointestinal hamartomas, fibrocystic disease of the breast, lipomas, fibromas, and genitourinary tumors or malformations.^29,30

For operational diagnosis in a person, mucocutaneous lesions alone can be sufficient if specific conditions are met, such as having six or more facial papules with three or more being trichilemmomas, or combinations of cutaneous facial papules, oral mucosal papillomatosis, and acral keratoses. Alternatively, diagnosis can be based on two major criteria, one major and three minor criteria, or four minor criteria.^29,30

For operational diagnosis in a family, the presence of pathognomonic criteria, any one major criterion with or without minor criteria, or two minor criteria can be sufficient.²⁹

The National Comprehensive Cancer Network (NCCN) adopted these criteria to ensure accurate diagnosis and management of CS, The NCCN continues to refine them based on new clinical and genetic information and currently hold the most up-to-date criteria for diagnosing CS and other PHTS disorders.^3,29,31

Pilarski, et al. (2013) published revised evidence-based criteria covering the spectrum of PTEN-related clinical disorders. The revised guidelines define the operational diagnosis of PTEN Hamartoma Tumor syndrome (PHTS) in an individual who meets either one of the following:

• Three or more major criteria, but one must include macrocephaly, LDD, or gastrointestinal hamartomas; or
• Two major and three minor criteria

The operational diagnosis in a family where one individual meets the revised PHTS clinical diagnostic criteria or has a PTEN mutation is as follows: 

• Any two major criteria with or without minor criteria; or
• One major and two minor criteria; or
• Three minor criteria³²

Pilarski, et al. (2013) defined the major and minor criteria as follows:

Major Criteria:

• Breast Cancer
• Endometrial cancer (epithelial)
• Thyroid Cancer (follicular)
• Gastrointestinal hamartomas (including ganglioneuromas, adenomas, hyperplastic polyps; ≥3)
• LDD (adult)
• Macrocephaly (megalocephaly) (i.e., ≥97th percentile, 58 cm in adult women, 60 cm in adult men)
• Macular pigmentation of 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) 4 – GT63
• 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
• ≥3 esophageal glycogenic acanthoses
• Lipomas (≥3)
• Intellectual disability (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)³²

The National Comprehensive Cancer Network (NCCN)
The NCCN guidelines for Cowden Syndrome/PHTS recommend testing in individuals who meet any of the following criteria:

• “Individual from a family with a known PTEN^ff P/LP variant
• Individual with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS)
• Individual meeting clinical diagnostic criteria for CS/PHTS
• Individual not meeting the clinical diagnostic criteria for CS/PHTS with a personal history of:
  • Adult Lhermitte-Duclos disease (cerebellar tumors); or
  • Autism spectrum disorder and macrocephaly; or
  • Two or more biopsy-proven trichilemmomas; or
  • Two or more major criteria (one must be macrocephaly); or
  • Three major criteria, without macrocephaly; or
  • One major and ≥3 minor criteria;^qq or
  • >4 minor criteria
• individual with a relative with a clinical diagnosis of CS/PHTS or BRRS for whom testing has not been performed
  • individual must have the following:
    • Two Any one major criterion, OR
    • Two minor criteria
  • PTEN P/LP variant detected by tumor genomic testing on any tumor type in the absence of germline analysis^rr”³

The relevant superscripts are captured below.

“^ffWhen this gene is included as part of a multi-gene panel, an individual does not need to meet these testing criteria if testing criteria on other testing criteria pages are met. 

^qqIf an individual has two or more major criteria, such as breast cancer and nonmedullary thyroid cancer, but does not have macrocephaly, one of the major criteria may be included as one of the three minor criteria to meet testing criteria.

^rrThis should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic PTEN pathogenic/likely pathogenic variants are common in many tumor types in absence of germline pathogenic/likely pathogenic variant.”3

Aforementioned major and minor testing criteria are reported below.
 

“Major Testing Criteria:

• Breast cancer
• Endometrial cancer (epithelial)
• Follicular thyroid cancer
• ≥3 GI hamartomas or ganglioneuromas^ss
• Macrocephaly (megalocephaly) (ie, ≥97%, 58 cm in adult female, 60 cm in adult male)
• Macular pigmentation of glans penis
• Mucocutaneous lesions^uu
  • Trichilemmoma (≥3, at least 1 biopsy-proven)
  • ≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)
  • ≥3 mucocutaneous neuromas
  • Oral papillomas (particularly on tongue and gingiva)(≥3 or 1 biopsy-proven or dermatologist diagnosed)

Minor Testing Criteria:^vv

• Autism spectrum disorder
• Colon cancer
• ≥3 Esophageal glycogenic acanthoses
• ≥3 Lipomas
• Intellectual disability (ie, IQ ≤75)
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid structural lesions (e.g., adenoma nodule[s], goiter)
• Renal cell carcinoma
• Single GI hamartoma or ganglioneuroma
• Testicular lipomatosis
• Vascular anomalies (including multiple intracranial developmental venous anomalies)”³

The relevant superscripts are captured below.

^“ssMultiple polyp types are often seen in patients with PHTS, and less commonly may include adenomas, hyperplastic polyps, and other histologies.

^uuThe literature available on mucocutaneous lesions is not adequate to accurately specify the number or extent of mucocutaneous lesions required to be a major criterion for CS/PHTS. Clinical judgment should be used.

^vvevidence exists in the literature to include fibrocystic disease of the breast, fibromas, and uterine fibroids as diagnostic criteria”³

The NCCN also notes that “Melanoma is also associated with PTEN but is not included in the testing criteria.”³

In their section outlining the “REVISED CLINICAL DIAGNOSTIC CRITERIA FOR PTEN HAMARTOMA TUMOR SYNDROME,” the NCCN recommends the following:

“Operational diagnosis in an individual (either of the following):

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

Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN P/LP variant:

1. Any two major criteria with or without minor criteria; or
2. One major and two minor criteria; or
3. Three minor criteria.”³

ClinGen PTEN Expert Panel 
This expert panel was convened by the ClinGen Hereditary Cancer Clinical Domain Working Group to develop PTEN-specific genetic variant interpretations. A total of 42 variants were included in the following categories: benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS), and conflicting (CONF) ClinVar assertions.

The following variants were considered BEN/LBEN: 9C>G, 903G>A, 1026C>A, 1311T>C, 18A>G, 75G>A, 132C>T, 360A>G, 1104T>G, 79+35C>T, 165-13_165-10delGTTT, 254-39G>T, 801+23G>A, and 1026+32T>G.

The following variants were considered PATH/LPATH: 50_51delAA, 511C>T, 892C>T, 964A>T, 987_990delTAAA, 80-1G>C, 165-1G>A, 493-2A>G, 801+1delG, 802-2A>T, 1026+1G, 103A>G, 389G>A, 407G>A, 517C>T, and 737C>T.

The following variants were considered VUS or CONF: 1170C>T, 209+3A>T, 235G>A, 304_306dupAAA, 1052_1054delTAG, 1171C>T, 764G>A, 44G>A, 78C>T, 209+4_209+7delAGTA, 521A>G.³³

American College of Medical Genetics (ACMG)
In 2013, the ACMG published guidelines for identifying the etiology of ASDs. These guidelines state that “PTEN testing [should] be reserved for patients with ASDs with a head circumference above the 98th percentile.”¹⁷ The authors then suggest that of all ASD-related genetic evaluations, about 5% of testing will be due to PTEN mutations.

National Organization for Rare Disorders (NORD) 
The NORD asserts that “The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas) and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.”³⁴ However, some noteworthy sign and symptoms that indicate PTEN genetic testing are captured below.

• “A small percentage of adults develop a rare tumor known as a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease). Symptoms of Lhermitte-Duclos disease include increased intracranial pressure, impaired ability to coordinate voluntary movements (ataxia) and seizures. It is rare when a person with adult-onset Lhermitte-Duclos does not have an underlying PTEN variant, and observing this tumor type is an automatic indicator for PTEN genetic testing.”
• “Macrocephaly (large head size) is found in 94% of measured patients with PHTS and can be a helpful screening tool to identify patients for PTEN genetic testing. In most patients, large head size is caused by overgrowth of brain tissue. The head shape may also be longer than average relative to width in some individuals (dolicocephaly).”³⁴

The authors go further to state that “Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally)….The overlap of neurodevelopmental disabilities and macrocephaly in both PHTS and Sotos syndrome indicates the need for genetic testing to avoid misdiagnosis.”³⁴ Genetic counseling is also suggested.

The authors report that “A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings.” Recently, a variant risk calculator has been developed which can estimate the risk for adults to have a PTEN variant based on their personal history characteristics; this tool is available online at https://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a variant of the PTEN gene is identified.³⁴

The current suggested screening regimens by age include:

 “Children (under age 18)

• Yearly thyroid ultrasound starting at 7 years of age
• Yearly skin check with physical examination
• Consider neurodevelopmental evaluation

Adults

• Monthly breast self-examination starting at age 18 years
• Yearly thyroid ultrasound and dermatologic evaluation
• Females: breast screening (at minimum mammogram) yearly beginning at age 35; MRI may also be incorporated
• Females: consider endometrial cancer screening starting at age 35 years. Personalized management including endometrial biopsy every 1 – 2 years and transvaginal ultrasound as needed (postmenopausal)
• Colonoscopy beginning at age 35 (unless symptomatic or close relative with colon cancer before age 40 years); colonoscopy frequency every 5 years; more frequently if symptomatic or polyps are found
• Biannual (every other year) renal imaging (CT or MRI preferred) beginning at age 40

For patients with a family history of a particular cancer type, screening may be considered 5 – 10 years prior to the youngest diagnosis in the family. For example, a patient whose mother developed breast cancer at 30 may begin breast surveillance at age 25 – 30”³⁴

American College of Gastroenterology (ACG) 
In 2015, the ACG published guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes. These guidelines clearly state that the “Genetic evaluation of a patient with possible CS should include testing for PTEN mutations… CS is caused by mutations in the PTEN gene. Once a disease-causing mutation is identified in a patient with CS or related conditions, other family members should undergo mutation-specific testing to determine whether the disease is present or absent so that appropriate surveillance can be undertaken.”³⁵ Further, the ACG also notes that “Surveillance in affected or at-risk CS patients should include screening for colon, stomach, small bowel, thyroid, breast, uterine, kidney, and skin (melanoma) cancers (conditional recommendation, low quality of evidence).”³⁵

The Japan Society of Coloproctology
The Japan Society for Coloproctology, in conjunction with several leading Japanese medical institutions, has developed a comprehensive set of guidelines for the diagnosis and management of Cowden Syndrome/PHTS in children and adults. These guidelines incorporate contributions from specialists in gastroenterology, oncology, pediatrics, dermatology, genetic medicine, and other related fields.

“This guideline adopted the NCCN criteria for diagnosis of CS/PHTS, which included 8 major criteria and 10 minor criteria, including clinical manifestations and PTEN testing criteria.”³⁶

Key recommendations from the joint guideline include the following:

• “We strongly recommend referral to a dermatologist to assess the presence of mucocutaneous lesions associated with PHTS.
• As the risk of developing colorectal cancer is higher in patients with this syndrome than in the general population, resection of colorectal polyps, which are considered precancerous lesions, is weakly recommended. There is no existing evidence to confirm whether resection of colorectal polyps inhibits the development of colorectal cancer and improves its prognosis.
• Owing to the high risk of developing breast cancer in women with this syndrome, breast surveillance using mammography or contrast-enhanced MRI is strongly recommended.
• Genetic testing for PTEN is recommended for patients with suspected CS/PHTS, considering the benefits for definitive diagnosis of this syndrome and for cancer surveillance.”³⁶

References  

1.   Lamis Yehia E, C. PTEN Hamartoma Tumor Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews((R)). University of Washington, Seattle 2016. https://www.ncbi.nlm.nih.gov/books/NBK1488/

2.   Stanich PP, Roberts ME. PTEN hamartoma tumor syndromes, including Cowden syndrome. Updated October 31, 2024. https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome

3.   NCCN. Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Updated March 6, 2025. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

4.   Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jul 15 2004;22(14):2954-63. doi:10.1200/jco.2004.02.141

5.   Ngeow J, Eng C. PTEN in Hereditary and Sporadic Cancer. Cold Spring Harb Perspect Med. Apr 1 2020;10(4)doi:10.1101/cshperspect.a036087

6.   Martín-Valbuena J, Gestoso-Uzal N, Justel-Rodríguez M, et al. PTEN hamartoma tumor syndrome: Clinical and genetic characterization in pediatric patients. Childs Nerv Syst. Jun 2024;40(6):1689-1697. doi:10.1007/s00381-024-06301-2

7.   Eng C. PTEN Hamartoma Tumor Syndrome. GeneReviews. University of Washington, Seattle; 2016. https://www.ncbi.nlm.nih.gov/pubmed/

8.   Pilarski R. PTEN Hamartoma Tumor Syndrome: A Clinical Overview. Cancers (Basel). Jun 18 2019;11(6)doi:10.3390/cancers11060844

9.   Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Human molecular genetics. Aug 1999;8(8):1461-72.

10. Mingo J, Rodriguez-Escudero I, Luna S, et al. A pathogenic role for germline PTEN variants which accumulate into the nucleus. European journal of human genetics : EJHG. Apr 30 2018;doi:10.1038/s41431-018-0155-x

11. Pilarski R, Stephens JA, Noss R, Fisher JL, Prior TW. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. Journal of medical genetics. Aug 2011;48(8):505-12. doi:10.1136/jmg.2011.088807

12. Tan MH, Mester J, Peterson C, et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. American journal of human genetics. Jan 07 2011;88(1):42-56. doi:10.1016/j.ajhg.2010.11.013

13. Giorgianni A, Pellegrino C, De Benedictis A, et al. Lhermitte-Duclos disease. A case report. Neuroradiol J. Dec 2013;26(6):655-60. doi:10.1177/197140091302600608

14. Garofola C, Gross GP. Cowden Disease (Multiple Hamartoma Syndrome). StatPearls. StatPearls Publishing LLC.; 2023.

15. Lachlan KL, Lucassen AM, Bunyan D, Temple IK. Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. Journal of medical genetics. Sep 2007;44(9):579-85. doi:10.1136/jmg.2007.049981

16. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. Oct 2009;11(10):687-94. doi:10.1097/GIM.0b013e3181ac9aea

17. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. May 2013;15(5):399-407. doi:10.1038/gim.2013.32

18. Ambry. PTEN-related Disorders. https://www.ambrygen.com/providers/genetic-testing/130/oncology/pten-related-disorders

19. GeneDx. PTEN Gene Analysis in PTEN Hamartoma Tumor Syndrome. Updated July 2021. https://providers.genedx.com/Resources/TIS-Files/TIS-195.pdf

20. Invitae. Invitae PTEN-Related Disorders Test. Labcorp. https://www.invitae.com/us/providers/test-catalog/gene-20432

21. Blueprint. PTEN Single Gene Test.  October  https://blueprintgenetics.com/tests/single-gene-tests/pten-single-gene-test-2/

22. Yehia L, Ni Y, Sesock K, et al. Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS genetics. Apr 2018;14(4):e1007352. doi:10.1371/journal.pgen.1007352

23. Ngeow J, Liu C, Zhou K, Frick KD, Matchar DB, Eng C. Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 10 2015;33(23):2537-44. doi:10.1200/jco.2014.60.3456

24. CC. Cleveland Clinic PTEN Risk Calculator. https://www.lerner.ccf.org/gmi/ccscore/

25. Isik E, Simsir OS, Solmaz AE, et al. Clinical and molecular aspects of PTEN mutations in 10 pediatric patients. Ann Hum Genet. Mar 12 2020;doi:10.1111/ahg.12380

26. Jonker LA, Lebbink CA, Jongmans MCJ, et al. Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome. Eur Thyroid J. Sep 2020;9(5):234-242. doi:10.1159/000508872

27. Baran JA, Tsai SD, Isaza A, et al. The Clinical Spectrum of PTEN Hamartoma Tumor Syndrome: Exploring the Value of Thyroid Surveillance. Horm Res Paediatr. Apr 22 2021:1-9. doi:10.1159/000515731

28. Cummings K, Watkins A, Jones C, Dias R, Welham A. Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics. J Neurodev Disord. Jan 4 2022;14(1):1. doi:10.1186/s11689-021-09406-w

29. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Journal of medical genetics. 2000;37(11):828. doi:10.1136/jmg.37.11.828

30. Eng C. Cowden Syndrome. J Genet Couns. Jun 1997;6(2):181-92. doi:10.1023/a:1025664119494

31. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the &lt;em&gt;PTEN&lt;/em&gt; hamartoma tumour syndrome. Journal of medical genetics. 2004;41(5):323. doi:10.1136/jmg.2004.018036

32. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. Journal of the National Cancer Institute. Nov 06 2013;105(21):1607-16. doi:10.1093/jnci/djt277

33. Mester JL, Ghosh R, Pesaran T, et al. Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Human mutation. Nov 2018;39(11):1581-1592. doi:10.1002/humu.23636

34. NORD. PTEN Hamartoma Tumor Syndrome. 7 https://rarediseases.org/rare-diseases/pten-hamartoma-tumor-syndrome/

35. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Feb 2015;110(2):223-62; quiz 263. doi:10.1038/ajg.2014.435

36. Takayama T, Muguruma N, Igarashi M, et al. Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication. J Anus Rectum Colon. 2023;7(4):284-300. doi:10.23922/jarc.2023-028

Coding Section 

CPT	Code Description
81321	PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis
81322	PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant
81323	PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant
0235U	PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions Proprietary test: Genomic Unity® PTEN Analysis Lab/Manufacturer: Variantyx Inc.

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/30/2025	Annual review, updating major and minor testing criteria in note 1. Also updating description, rationale, and references.
07/30/2024	Annual review, no change to policy intent. Updating description, table of terminology, rationale, references and coding.
01/24/2024	Annual review, no change to policy intent, but, policy rewritten for clarity and consistency. Also updating description, rationale and references.
11/13/2023	Updated annual review to 01/01/2024.
08/07/2023	Updated annual review to 10/01/2023.
07/10/2023	Moving review date to September. No other changes.
08/02/2022	Annual review, policy rewritten for clarity, new note #1 added, coverage criteria #6 updated regarding pathogenic variants. Also updating coding, description, rationale and references.
11/23/2021	Updated coding. Added code 0235U to coding section. No other changes made.
07/29/2021	Annual review, updating policy to include medical necessity coverage in #5 for Bannayan-Riley_Ruvalcaba syndrome, no other changes to intent. Also updating rationale and references.
07/15/2020	Annual review, updating policy to include genetic counseling, and medical necessity criteria for additional testing. Also updating background, rationale and references.
07/12/2019	Annual review, no change to policy intent. Adding note directing reader to CAM 204115 if needed.
07/19/2018	Annual review, no change to policy intent. Updating coding.
07/19/2017	Annual review, major revision of policy verbiage to increase clarity. No other changes made.
04/25/2017	Updated category to Laboratory. No other changes.
04/03/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
04/13/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
04/15/2015	Annual review, no change to policy intent. Updating background, description, rationale and references. Added regulatory status and coding.
03/31/2014	New Policy