Medical Policy

Policy Num:      11.003.016
Policy Name:    Genetic Testing for PTEN Hamartoma Tumor Syndrome
Policy ID:          [11.003.016]  [Ac / B / M+ / P+]  [2.04.88]

Last Review:      March 10, 2025
Next Review:      March 20, 2026
 

Related Policies: None

Genetic Testing for PTEN Hamartoma Tumor Syndrome

summary

Description

The PTEN hamartoma tumor syndrome (PHTS) includes several syndromes with heterogeneous clinical symptoms, which may place individuals at an increased risk for the development of certain types of cancer. Genetic testing for PTEN can confirm a diagnosis of PHTS.

Summary of Evidence

For individuals who have clinical signs and/or symptoms of a PTEN hamartoma tumor syndrome (PHTS) or who are asymptomatic with a first-degree relative with a PHTS and a known familial variant who receive genetic testing for a PTEN familial variant, the evidence includes case series and a large prospective study on the frequency of a PTEN variants in individuals meeting clinical criteria for a PHTS, and studies of cancer risk estimates in individuals with a PTEN disease-associated variant. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and morbid events. The published clinical validity of testing for the PTEN gene is variable. The true clinical validity is difficult to ascertain because the syndrome is defined by the presence of a PTEN disease-associated variant. The sensitivity of tests for Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome has been reported to be up to 80% and 60%, respectively. Direct evidence of the clinical utility of genetic testing for PTEN is lacking; however, confirming a diagnosis in a patient with clinical signs of a PHTS will lead to changes in clinical management by increasing surveillance to detect cancers associated with PHTS at an early and treatable stage. Although most cases of a PHTS occur in individuals with no known family history of PHTS, testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether genetic testing improves the net health outcome in individuals with clinical signs and/or symptoms of a PTEN hamartoma tumor syndrome or asymptomatic or at-risk individuals with a known familial variant.

POLICY

Genetic testing for PTEN may be considered medically necessary to confirm the diagnosis when a patient has clinical signs of a PTEN hamartoma tumor syndrome.

Targeted genetic testing for a PTEN familial variant may be considered medically necessary in a first-degree relative of a proband with a known PTEN pathogenic variant.

Genetic testing for PTEN is considered investigational for all other indications.

POLICY GUIDELINES

Testing Strategy to Confirm a Diagnosis in a Proband

The order of testing to optimize yield would be (1) sequencing of PTEN exons 1-9 and flanking intronic regions. If no disease-associated variant is identified, perform (2) deletion/duplication analysis. If no disease-associated variant is identified, consider (3) promoter analysis, which detects disease-associated variants in approximately 10% of individuals with Cowden syndrome who do not have an identifiable disease-associated variant in the PTEN coding region.

Testing a First-Degree Relative

When a PTEN disease-associated variant has been identified in the proband, testing of asymptomatic at-risk relatives can identify those family members who have the familial variant, for whom an initial evaluation and ongoing surveillance should be performed.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign" - to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

 ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

PTEN Hamartoma Tumor Syndromes

PTEN hamartoma tumor syndrome (PHTS) is characterized by hamartomatous tumors and PTEN germline disease-associated variants. Clinically, PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (PLS).

CS is a multiple hamartoma syndrome with a high-risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by age late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years.^1, The lifetime risk for thyroid cancer, usually follicular carcinoma is approximately 35%. The risk for endometrial cancer is not well-defined but may approach 28%. A 2012 study included 3399 prospectively recruited individuals who met relaxed International Cowden Consortium PHTS criteria; 368 were found to have PTEN disease-associated variants.^2, Estimated lifetime cancer risks were: 85.2% for breast (95% confidence interval [CI], 71.4% to 99.1%); 35.2% for thyroid; (95% CI, 19.7% to 50.7%); 28.2% for endometrium (95% CI, 17.1% to 39.3%); 9.0% for colorectal (95% CI, 3.8% to 14.1%); 33.6% for kidney (95% CI, 10.4% to 56.9%); and 6% for melanoma (95% CI, 1.6% to 9.4%). A 2013 study of 154 individuals with a PTEN disease-associated variant found cumulative cancer risks at age 70 of 85% (95% CI, 70% to 95%) for any cancer, 77% (95% CI, 59% to 91%) for female breast cancer, and 38% (95% CI, 25% to 56%) for thyroid cancer.^3,

BRRS is characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. Additional features include high birth weight, developmental delay and mental deficiency (50% of affected individuals), a myopathic process in proximal muscles (60%), joint hyperextensibility, pectus excavatum, and scoliosis (50%).

PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.

PLS is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

CS is the only PHTS disorder associated with a documented predisposition to cancer; however, it has been suggested that patients with other PHTS diagnoses associated with PTEN variants should be assumed to have cancer risks similar to CS.

Clinical Diagnosis

A presumptive diagnosis of PHTS is based on clinical findings; however, because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN disease-associated variant is identified.

Diagnostic Criteria for Cowden Syndrome

The International Cowden Consortium has developed criteria for diagnosing CS (see Table 1).^4,

Table 1. Diagnostic Criteria for Cowden Syndrome^a

 Adapted from Blumenthal et al (2008).4, a These criteria for diagnosing Cowden syndrome have been adopted by the National Comprehensive Cancer Network.

In 2013, a systematic review assessed the clinical features reported in individuals with a PTEN disease-associated variant and proposed revised diagnostic criteria.^5, Reviewers concluded that there was insufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was sufficient evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies, and many of these clinical features are included in CS testing minor criteria in the National Comprehensive Cancer Network guidelines on genetic/familial high-risk assessment of breast and ovarian (v.2.2024 ).^6,

Bannayan-Riley-Ruvalcaba Syndrome

Diagnostic criteria for BRRS have not been established. Current diagnostic practices are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis.

Proteus Syndrome

PS appears to affect individuals in a mosaic distribution (ie, only some organs/tissues are affected). Thus, it is frequently misdiagnosed, despite the development of consensus diagnostic criteria. Mandatory general criteria for diagnosis include mosaic distribution of lesions, progressive course, and sporadic occurrence. Additional specific criteria for diagnosis as listed in Table 2.^7,

Table 2. Diagnostic Criteria for Proteus Syndrome

 Adapted from Biesecker (2006).7,

Proteus-Like Syndrome

Proteus-Like Syndrome (PLS) is undefined but describes individuals with significant clinical features of PS not meeting the diagnostic criteria.

Molecular Diagnosis

PTEN (phosphatase and tens in homolog deleted on chromosome 10) is a tumor suppressor gene on chromosome 10q23 and is a dual-specificity phosphatase with multiple but incompletely understood roles in cellular regulation.^8,PTEN is the only gene for which disease-associated variants are known to cause PHTS. PTEN disease-associated variants are inherited in an autosomal dominant manner.

Most CS cases are simplex. However, because CS is likely underdiagnosed, the actual proportion of simplex cases (ie, individuals with no obvious family history) and familial cases (ie, ≥2 related affected individuals) cannot be determined. It is estimated that 50% to 90% of cases of CS are de novo and approximately 10% to 50% of individuals with CS have an affected parent.

Because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN disease-associated variant is identified. Up to 85% of patients who meet the clinical criteria for a diagnosis of CS and 65% of patients with a clinical diagnosis of BRRS have a detectable PTEN disease-associated variant. Some data have suggested that up to 20% of patients with PS and up to 50% of patients with a PLS have PTEN disease-associated variants.

Most of these disease-associated variants can be identified by sequence analysis of the coding and flanking intronic regions of genomic DNA. A smaller number of variants are detected by deletion/duplication or promoter region analysis.

Penetrance

More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses.

Management

Treatment

Treatment of the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts (ie, chemotherapy, surgery, and/or radiotherapy as per usual guidelines and clinical practice).

Surveillance

The most serious consequences of a diagnosis of PHTS relates to the increased risk of cancers, including breast, thyroid, and endometrial, and, to a lesser extent, renal. Therefore, the most important aspect of management of an individual with a PTEN disease-associated variant is increased cancer surveillance to detect tumors at the earliest, most treatable stages.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratory testing for PTEN variants is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

RATIONALE

This evidence review was created in February 2013 with searches of the PubMed database. The most recent literature update was performed through December 13, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Testing in Patients with Signs and/or Symptoms of PTEN Hamartoma Tumor Syndrome

Clinical Context and Test Purpose

The purpose of genetic testing of patients who have signs and/or symptoms of PTEN hamartoma tumor syndrome (PHTS) is to confirm a diagnosis and inform management decisions such as increased cancer surveillance.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with clinical signs and/or symptoms of a PHTS.

Interventions

The test being considered is genetic testing for PTEN. Patients may be referred from primary care to an oncologist or medical geneticist for investigation and management of PHTS. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Comparators

The following practices are currently being used: standard clinical management without genetic testing for PTEN.

Outcomes

The potential beneficial outcomes of primary interest would be improvements in short-term and long-term overall survival and disease-specific survival and reductions in morbid events. Increased cancer surveillance in patients with a PTEN pathogenic variant is initiated to detect the presence of cancer at earlier and more treatable stages.

Potential harmful outcomes are those resulting from a false-positive or false-negative test. False-positive test results can lead to unnecessary cancer surveillance procedures (eg, invasive biopsies). False-negative test results can lead to lack of cancer surveillance that might detect cancer at earlier and more treatable stages.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Many reports on the prevalence of the features of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) have been based on data compiled from case reports and studies of small cohorts. Most of these reports were published before adoption of the International Cowden Consortium diagnostic criteria for CS in 1996 (see Table 1), and the true frequencies of the clinical features in CS and BRRS are unknown.^8,

According to a large reference laboratory, the clinical sensitivity of PTEN-related disorder sequencing is 80% for CS, 60% for BRRS, 20% for PTEN-related Proteus syndrome, and 50% for Proteus-like syndrome. For PTEN-related deletions and duplications, it is up to 10% for BRRS and unknown for CS, Proteus syndrome, and Proteus-like syndrome.^9,

Germline PTEN disease-associated variants have been identified in approximately 80% of patients meeting diagnostic criteria for CS and in 50% to 60% of patients with a diagnosis of BRRS, using sequencing analysis using polymerase chain reaction of the coding and flanking intronic regions of the gene.^10,11, Marsh et al (1998) screened DNA from 37 CS families, and PTEN disease-associated variants were identified in 30 (81%) of 37 CS families, including single nucleotide variants, insertions, and deletions.^10, Whether the remaining patients have undetected PTEN disease-associated variants or disease-associated variants in other, unidentified genes, is unknown.^12,

A study by Pilarski et al. (2011) determined the clinical features most predictive of a disease-associated variant in a cohort of patients undergoing PTEN testing.^8, Molecular and clinical data were reviewed for 802 patients referred for PTEN analysis to a single-laboratory. All patients were classified by whether they met revised International Cowden Consortium diagnostic criteria. Two hundred thirty of the 802 patients met diagnostic criteria for CS. Of these, 79 had a PTEN disease-associated variant, for a detection rate of 34%. The authors commented that this disease-associated variant frequency was significantly lower than previously reported, possibly suggesting that the clinical diagnostic criteria for CS are not as robust at identifying patients with germline PTEN disease-associated variants as previously thought. In their study, of the patients meeting diagnostic criteria for BRRS, 23 (55%) of 42 had a disease-associated variant, and 7 (78%) of 9 patients with diagnostic criteria for both CS and BRRS had a disease-associated variant, consistent with the literature.

Section Summary: Clinically Valid

Evidence from several small studies has indicated that the clinical sensitivity of genetic testing for PTEN may be highly variable. This may reflect the phenotypic heterogeneity of the syndromes and an inherent referral bias because patients with more clinical features of CS and BRRS are more likely to get tested. The true clinical specificity is uncertain because the syndrome is defined by the disease-associated variant.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

The clinical utility for patients with suspected PHTS depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. There is no direct evidence for the clinical utility of genetic testing in these patients because no studies were identified describing how a molecular diagnosis of PHTS changed patient management.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

For patients diagnosed with PHTS by identifying a PTEN disease-associated variant, the medical management focuses on increased cancer surveillance to detect tumors at the earlier, more treatable stages.

Section Summary: Clinically Useful

Direct evidence of the clinical utility of PTEN testing is lacking. However, the clinical utility of genetic testing for PTEN is that genetic testing can confirm the diagnosis in patients with clinical signs and/or symptoms of PHTS. Management changes include increased surveillance for the cancers associated with these syndromes.

For individuals who have clinical signs and/or symptoms of a PHTS or who are asymptomatic with a first-degree relative with a PHTS and a known familial variant who receive genetic testing for a PTEN familial variant, the evidence includes case series and a large prospective study on the frequency of a PTEN variants in individuals meeting clinical criteria for a PHTS, and studies of cancer risk estimates in individuals with a PTEN disease-associated variant. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and morbid events. The published clinical validity of testing for the PTEN gene is variable. The true clinical validity is difficult to ascertain, because the syndrome is defined by the presence of a PTEN disease-associated variant. The sensitivity of tests for CS and BRRS has been reported to be up to 80% and 60%, respectively. Direct evidence of the clinical utility of genetic testing for PTEN is lacking; however, confirming a diagnosis in a patient with clinical signs of a PHTS will lead to changes in clinical management by increasing surveillance to detect cancers associated with PHTS at an early and treatable stage. Although most cases of a PHTS occur in individuals with no known family history of PHTS, testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 2

Familial Variant Testing of Asymptomatic Individuals

Clinical Context and Test Purpose

The purpose of familial variant testing of asymptomatic individuals with a first-degree relative with a PHTS is to screen for the family-specific pathogenic variant to inform management decisions (eg, increased cancer surveillance) or to exclude asymptomatic individuals from increased cancer surveillance.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is asymptomatic individuals with a first-degree relative who has a PHTS.

Interventions

The test being considered is targeted genetic testing for a PTEN familial variant.

Comparators

The following practices are currently being used: standard clinical management without targeted genetic testing for a PTEN familial variant.

Outcomes

The potential beneficial outcomes of primary interest would be improvement in overall survival and disease-specific survival and reductions in morbid events. Increased cancer surveillance in patients with a PTEN familial variant is initiated to detect the presence of cancer at earlier and more treatable stages. Asymptomatic individuals who test negative for a PTEN familial variant can be excluded from increased cancer surveillance.

The potential harmful outcomes are those resulting from a false-positive or false-negative test. False-positive test results can lead to unnecessary cancer surveillance procedures (eg, invasive biopsies). False-negative test results can lead to lack of cancer surveillance that may detect cancer at earlier and more treatable stages.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

See the discussion in the previous section for patients with signs and/or symptoms of PHTS.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified assessing the clinical usefulness of testing asymptomatic individuals with a first-degree relative who has a diagnosis of PHTS.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

When a PTEN disease-associated variant has been identified in a proband, testing of first-degree relatives can identify those who also have the familial variant and PHTS. These individuals require an initial evaluation and ongoing cancer surveillance. Alternatively, first-degree relatives who test negative for the familial variant would not require ongoing cancer surveillance.

Section Summary: Clinically Useful

Direct evidence of the clinical utility of familial variant testing in asymptomatic individuals is lacking. However, for first-degree relatives of PHTS in affected individuals, a positive test for a familial variant would confirm the diagnosis of PHTS and result in ongoing cancer surveillance. A negative test for a familial variant would reduce unnecessary cancer surveillance.

For individuals who are asymptomatic with a first-degree relative with a PTEN hamartoma tumor syndrome and a known familial variant

Supplemental Information

The purpose of the remaining sections in Supplemental Information is to provide reference material regarding existing practice guidelines and position statements, U.S. Preventive Services Task Force Recommendations and Medicare National Coverage Decisions and registered, ongoing clinical trials. Inclusion in the Supplemental Information does not imply endorsement and information may not necessarily be used in formulating the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

Current (v.2.2025 ), National Comprehensive Cancer Network guidelines on genetic/familial high-risk assessment for breast and ovarian cancer^6, include Testing Criteria for Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS) (CRIT-8 ) that recommend testing for:

• Individual from a family with a known PTEN pathogenic/likely pathogenic variant

• Individual with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS)

• Individual meeting clinical diagnostic criteria for CS/PHTS

• Individual not meeting clinical diagnostic criteria for CS/PHTS with a personal history of:

1. Adult Lhermitte-Duclos disease (cerebellar tumors); or 

2. autism spectrum disorder and macrocephaly; or

3. 2 or more biopsy-proven trichilemmomas; or 2 or more major criteria (1 must be macrocephaly); or

4. 3 major criteria, without macrocephaly; or

5. 1 major and ≥3 minor criteria; or ≥4 minor criteria

• At-risk individual with a relative with a clinical diagnosis of CS/PHTS or BRRS for whom testing has not been performed. The at-risk individual must have the following: Any 1 major criterion or 2 minor criteria.

• PTEN pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline analysis.

Additionally, the following is recommended for Cowden syndrome management (see Table 3).

Table 3. NCCN Guidelines on Cowden Syndrome / PTEN Hamartoma Tumor Syndrome Management

   CS: Cowden Syndrome; MRI: magnetic resonance imaging; PHTS: PTEN hamartoma tumor syndrome.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for genetic testing for PTEN hamartoma tumor syndrome have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in December 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

References

1. Eng C. PTEN Hamartoma Tumor Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2016.
2. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. Jan 15 2012; 18(2): 400-7. PMID 22252256
3. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. Apr 2013; 50(4): 255-63. PMID 23335809
4. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. Nov 2008; 16(11): 1289-300. PMID 18781191
5. Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. Nov 06 2013; 105(21): 1607-16. PMID 24136893
6. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Genetic/familial high risk assessment: breast and ovarian. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed December 13, 2024.
7. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. Nov 2006; 14(11): 1151-7. PMID 16883308
8. Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. Aug 2011; 48(8): 505-12. PMID 21659347
9. Yehia L and Eng C. PTEN Hamartoma Tumor Syndrome. GeneReviews. Updated May 4, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1488/. Accessed December 13, 2024.
10. Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. Mar 1998; 7(3): 507-15. PMID 9467011
11. 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. Hum Mol Genet. Aug 1999; 8(8): 1461-72. PMID 10400993
12. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. May 2004; 41(5): 323-6. PMID 15121767.

    Codes

    Codes	Number	Description
    CPT	81321	PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis
    	81322	PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant
    	81323	PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant
    		PLA panels that include PTEN testing
    	0101U	Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated [15 genes (sequencing and deletion/duplication), EPCAM and GREM1 (deletion/duplication only)]
    	0102U	Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated [17 genes (sequencing and deletion/duplication)]
    	0130U	Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), targeted mRNA sequence analysis panel (APC, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, and TP53) (List separately in addition to code for primary procedure) ,(Use 0130U in conjunction with 81435, 0101U)
    	0131U	Hereditary breast cancer–related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (13 genes) (List separately in addition to code for primary procedure) (Use 0131U in conjunction with 81162, 81432, 0102U)
    	0235U	PTEN (phosphatase and tensin homolog) (eg, 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
    ICD-10-CM	Q85.81	PTEN tumor syndrome
    	Q85.82	Other Cowden syndrome
    	Q85.83	Von Hippel-Lindau syndrome
    	Q85.9	Phakomatosis, unspecified (includes hamartosis NOS)
    	Z13.71	Encounter for nonprocreative screening for genetic disease carrier status
    	Z13.79	Encounter for other screening for genetic and chromosomal anomalies
    ICD-10-PCS		Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.
    Type of Service	Laboratory
    Place of Service	Outpatient/ Professional

    Applicable Modifiers

    As per Correct Coding Guidelines

    Policy History

    Date	Action	Description
    03/10/25	Annual Review	Policy updated with literature review through December 13, 2024; reference added. Policy statements unchanged.
    03/08/24	Annual Review	Policy updated with literature review through December 21, 2023; no references added. Policy statements unchanged.
    03/14/23	Annual Review	Policy updated with literature review through November 14, 2023; no references added. Minor editorial refinements to policy statements; intent unchanged.
    02/20/23	Replace policy - coding    update only	To add ICD10 85.81, Q85.82, Q85.83
    10/13/22	Replace policy - coding    update only	ICD 10 CM: Q85.8 deleted as of 9/30/2022
    03/15/22	Annual Review	Policy updated with literature review through November 15, 2021; no references added. Updated NCCN testing criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome. Policy statements unchanged.
    03/19/21	Annual Review	No changes
    03/11/20	Annual Review	No charges
    02/11/20	Annual Review	No changes
    02/11/19	Annual Review	No changes
    11/12/18	Revision
    02/12/18	Revision
    02/15/17	Revision