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    v1.0.31
    OpenPayerPolicy UpdatesGenetic & Molecular TestingRegence PTEN Genetic Testing Coverage | OpenPayer
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    CurrentRegence BlueCross BlueShieldPolicy 63

    Genetic Testing for PTEN Hamartoma Tumor Syndrome

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    This policy governs coverage of genetic testing for PTEN variants used to evaluate PTEN hamartoma tumor syndrome. Testing is medically necessary only when specified family-history or clinical criteria are met and required clinical documentation is submitted.

    Policy Summary
    PayerRegence BlueCross BlueShield
    PolicyGenetic Testing for PTEN Hamartoma Tumor Syndrome
    Policy CodePolicy N/A
    Change TypeNo material change
    Effective DateSeptember 1, 2026
    Last ReviewJul 1, 2026
    Next Review DateMay 1, 2027
    Key ActionSubmit documentation supporting the applicable medical-necessity criteria and required clinical records for prior authorization review.
    SourceLink
    POLICY UPDATE CHANGES

    No material clinical or coverage changes in this revision.

    1Gene specifically addressed
    2Primary medically necessary coverage populations
    InvestigationalOther indications
    4CPT and HCPCS codes listed

    OpenPayer is powered by Trek Health's payer performance platform. Trek continuously ingests, validates, and normalizes Transparency in Coverage data alongside payer policies and other commercial payer data to create a structured payer intelligence foundation. OpenPayer uses this foundation to deliver personalized search results, dynamically generated policy pages, and tailored policy monitoring based on each user's payers, specialties, billing codes, and areas of interest. The same intelligence powers broader payer performance workflows, including reimbursement benchmarking, contract evaluation, payer negotiations, and financial decision-making.

    Coverage Criteria

    Medically Necessary PTEN Testing

    Genetic testing for PTEN, including evaluation for PTEN hamartoma tumor syndrome, may be considered medically necessary when ONE or more of the following criteria are met:

    ONE or more of the following

    • The individual is a first-degree relative of a proband with a known PTEN disease-associated variant.

    • The individual has ONE or more of the following

      • Two or more biopsy-proven trichilemmomas.

      • Both of the following

        • Autism spectrum disorder.
        • Macrocephaly.
      • Adult Lhermitte-Duclos syndrome.

    • At least TWO of the following

      • Autism spectrum disorder.
      • Breast cancer.
      • Colon cancer.
      • Endometrial cancer (epithelial).
      • Esophageal glycogenic acanthoses, three or more.
      • Gastrointestinal hamartomas, including ganglioneuromas, adenomas, or hyperplastic polyps; three or more.
      • Intellectual disability defined as IQ less than or equal to 75.IQ <= 75

    Criteria Not Met

    If Criterion I is not met, PTEN genetic testing is considered investigational.

    The individual does not meet Criterion I for medically necessary PTEN testing.

    Medically Necessary Indications

    PTEN genetic testing may be considered medically necessary for either of the following qualifying populations:

    ONE of the following

    • An individual for whom a presumptive diagnosis of PTEN hamartoma tumor syndrome has been made based on clinical signs.
    • A first-degree relative of an individual with a known disease-associated PTEN variant.

    Investigational or Unproven Indications

    PTEN genetic testing is considered investigational for indications that do not meet the medical-necessity criteria.

    Testing for a PTEN variant for all other indications, including individuals who do not meet the policy criteria, is investigational or unproven.

    Genetic testing for PTEN is considered investigational when Criterion I is not met.

    Coding and Clinical Thresholds

    CPTCPT
    0235UPTEN (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
    81321PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis
    81322known familial variant; duplication/deletion variant
    HCPCSHCPCS
    81323None
    Macrocephaly
    Macrocephaly thresholdGreater than or equal to the 97th percentile
    Adult women58 cm circumference
    Adult men60 cm circumference
    Intellectual disability
    FindingIntellectual disability
    IQ thresholdLess than or equal to 75
    Policy definitionIntellectual disability is defined as IQ ≤75
    Esophageal glycogenic acanthoses
    FindingEsophageal glycogenic acanthoses
    Minimum countThree or more
    Clinical useListed as an associated finding in an adult with Lhermitte-Duclos syndrome
    Gastrointestinal hamartomas
    FindingGastrointestinal hamartomas, including ganglioneuromas, adenomas, and hyperplastic polyps
    Minimum countThree or more
    Clinical useListed as an associated finding in an adult with Lhermitte-Duclos syndrome
    Lipomas
    FindingLipomas
    Minimum countThree or more
    Clinical useListed as an associated finding in an adult with Lhermitte-Duclos syndrome
    Mucocutaneous lesions
    FindingMucocutaneous lesions
    Minimum countThree or more
    DocumentationClinical documentation is required

    Provider Actions and Review Requirements

    Prior Authorization

    Prior Authorization Required

    Prior authorization is required before PTEN genetic testing, including testing in the evaluation of PTEN hamartoma tumor syndrome. Submit clinical documentation supporting the applicable Criterion I medical-necessity pathway with the authorization request.

    • Include the clinical indication or qualifying familial PTEN variant context.
    • Submit supporting history, physical examination, chart notes, and current symptomology.
    Documentation Required

    Required Clinical Documentation

    The review submission must include sufficient clinical documentation to determine whether the policy criteria are met. Required documentation includes history and physical/chart notes, current symptomology, and documentation of a first-degree relative when a known pathogenic or likely pathogenic PTEN variant is present.

    • History and physical/chart notes
    • Current symptomology
    • Documentation of the first-degree relative and the known pathogenic/likely pathogenic variant, when applicable
    Documentation Required

    Document Clinical Indication or Familial Variant

    Document the clinical indication for testing by establishing a presumptive PTEN hamartoma tumor syndrome diagnosis based on clinical signs, or document that the individual is a first-degree relative of a proband with a known disease-associated PTEN variant.

    • For a presumptive diagnosis, provide the clinical findings supporting the diagnosis and the applicable Criterion I features.
    • For familial testing, provide documentation of the first-degree relationship and the known disease-associated PTEN variant.
    Denial Risk

    Criteria Not Met

    PTEN genetic testing is considered investigational when Criterion I medical-necessity criteria are not met. Testing that does not satisfy the applicable qualifying criteria may therefore be denied as investigational.

    • Confirm that the individual meets at least one Criterion I pathway before ordering testing.
    Denial Risk

    Missing Documentation May Affect Coverage

    If required clinical documentation is not submitted, it could impact the review and coverage decision. Missing information may prevent confirmation that the policy criteria are met and may result in an unfavorable determination.

    • Submit all required history and physical/chart notes, current symptomology, and applicable first-degree-relative documentation.
    Denial Risk

    Indications Outside Covered Populations

    PTEN genetic testing is considered investigational for indications outside the covered populations. This includes testing when there is neither a presumptive PTEN hamartoma tumor syndrome diagnosis based on clinical signs nor a first-degree-relative context involving a known disease-associated PTEN variant.

    • Covered population: individuals with a presumptive diagnosis based on clinical signs.
    • Covered population: first-degree relatives of an individual with a known disease-associated PTEN variant.
    • All other indications are considered investigational.
    Note

    Genetic Counseling and Family Considerations

    Consider genetic counseling before testing and discuss the implications of results with individuals and families. For at-risk relatives, assess whether testing is appropriate when a familial disease-associated PTEN variant is known; provide counseling to women of reproductive age regarding reproductive and familial implications.

    • Offer genetic counseling and testing considerations for at-risk first-degree relatives.
    • Counsel women of reproductive age about potential reproductive, familial, and surveillance implications of results.

    Clinical Background

    PTEN hamartoma tumor syndrome (PHTS) comprises clinically heterogeneous syndromes associated with germline disease-associated variants in the PTEN tumor suppressor gene. The spectrum includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome. Affected individuals may develop hamartomatous tumors and have increased risks of breast, thyroid, endometrial, and renal cancers. A definitive diagnosis is made when a PTEN disease-associated variant is identified.

    Definitions

    PTEN hamartoma tumor syndrome (PHTS)
    DefinitionA group of syndromes with heterogeneous clinical symptoms
    Clinical riskIndividuals may have an increased risk of developing certain types of cancer
    Diagnostic characteristicPHTS is diagnosed when a PTEN disease-associated variant is identified
    Proband
    DefinitionThe affected individual in whom a PTEN pathogenic variant has been identified
    Variant contextThe identified variant is the family-specific variant
    Family testingThe family-specific variant may be evaluated in relatives
    Pathogenic variant
    Sequence typeA DNA sequence change
    Sequence typeA protein sequence change
    Disease associationThe change is associated with disease
    Variant of uncertain significance
    DefinitionA genetic change
    Health effectIts effect on human health is unknown
    TerminologySuch changes are referred to as variants of uncertain significance
    Analytic validity
    DefinitionThe technical accuracy of a test
    Detecting variantsDetecting a pathogenic variant that is present
    Excluding variantsExcluding a variant that is absent
    Clinical validity
    DefinitionThe diagnostic performance of a test in detecting clinical disease
    Performance measuresIncludes sensitivity and specificity
    Predictive valuesIncludes positive and negative predictive values
    Clinical utility
    DefinitionThe extent to which diagnostic test results change patient management
    Management changesEvaluates how test results are used to change management
    Health outcomesEvaluates whether management changes produce clinically important improvements in health outcomes
    Pathogenic variant
    DefinitionA variant associated with disease
    Variant terminologyThe term variant describes a change in a DNA or protein sequence
    Clinical classificationPathogenic variants are distinguished from benign variants because they are associated with disease
    Variant of uncertain significance
    Sequence typeA DNA sequence change
    Sequence typeA protein sequence change
    Health effectsThe effects on human health are unknown

    Covered Testing Indications

    First-Degree Relative of a Proband With a Known PTEN Variant

    Testing may be considered medically necessary for an asymptomatic at-risk relative when the familial variant is known.

    Familial testing: The individual is a first-degree relative of a proband with a known PTEN disease-associated variant.

    Testing can identify the family-specific variant and support evaluation and ongoing surveillance for PTEN hamartoma tumor syndrome.

    Individual With Qualifying Clinical Findings

    Testing may be considered medically necessary when an individual has one or more of the following qualifying clinical findings.

    Qualifying clinical findings

    • Two or more biopsy-proven trichilemmomas.two or more
    • Autism spectrum disorder and macrocephaly.
    • Adult Lhermitte-Duclos syndrome.

    Adult Lhermitte-Duclos Syndrome With Associated Findings

    Testing may be considered medically necessary when an adult with Lhermitte-Duclos syndrome has at least two associated findings.

    Required clinical combination

    • Associated findings

      • Autism spectrum disorder.
      • Breast cancer.
      • Colon cancer.
      • Endometrial cancer (epithelial).
      • Esophageal glycogenic acanthoses, three or more.three or more

    Presumptive Diagnosis of PTEN Hamartoma Tumor Syndrome

    Testing may be considered medically necessary when clinical signs support a presumptive diagnosis of PTEN hamartoma tumor syndrome.

    Presumptive PHTS diagnosis: A presumptive diagnosis of PTEN hamartoma tumor syndrome has been made based on clinical signs.

    Testing may confirm the diagnosis and support increased surveillance for associated cancers.

    First-Degree Relative of an Individual With a Known PTEN Variant

    Testing may be considered medically necessary for a first-degree relative of an individual with a known disease-associated PTEN variant.

    Familial indication: The patient is a first-degree relative of an individual with a known disease-associated PTEN variant.

    Testing can identify relatives who have PTEN hamartoma tumor syndrome and need initial evaluation and ongoing surveillance.

    Eligibility Requirements

    For familial testing, the individual must be a first-degree relative of a proband with a known PTEN disease-associated variant. Documentation must identify the first-degree relationship and establish the known pathogenic or likely pathogenic PTEN variant in the affected family member.

    For prenatal testing, the disease-causing PTEN allele in the affected family member must be identified before testing can be performed.

    Not Covered and Investigational Testing

    PTEN genetic testing is not covered as medically necessary when Criterion I is not met. Testing is also considered investigational for indications outside the covered populations, including when the individual has neither a presumptive diagnosis of PTEN hamartoma tumor syndrome based on clinical signs nor first-degree relationship to an individual with a known disease-associated PTEN variant.

    Policy Summary
    PayerRegence BlueCross BlueShield
    PolicyGenetic Testing for PTEN Hamartoma Tumor Syndrome
    Policy CodePolicy N/A
    Change TypeNo material change
    Effective DateSeptember 1, 2026
    Last ReviewJul 1, 2026
    Next Review DateMay 1, 2027
    Key ActionSubmit documentation supporting the applicable medical-necessity criteria and required clinical records for prior authorization review.
    SourceLink
    On This Page
    Coverage CriteriaCoding and Clinical ThresholdsProvider Actions and Review RequirementsClinical BackgroundDefinitionsCovered Testing IndicationsEligibility RequirementsNot Covered and Investigational Testing
  1. Lipomas, three or more.
  2. Macrocephaly (megalocephaly), defined as greater than or equal to the 97th percentile; 58 cm in an adult woman or 60 cm in an adult man.>= 97th percentile
  3. Macular pigmentation of the glans penis.
  4. Mucocutaneous lesions, three or more, with clinical documentation.
  5. Renal cell carcinoma.
  6. Testicular lipomatosis.
  7. Thyroid cancer or thyroid structural lesions, such as adenoma or multinodular goiter.
  8. Vascular anomalies, including multiple intracranial developmental venous anomalies.
  9. Gastrointestinal hamartomas, including ganglioneuromas, adenomas, or hyperplastic polyps, three or more.three or more
  10. Intellectual disability defined as IQ less than or equal to 75.IQ ≤75
  11. Lipomas, three or more.three or more
  12. Macrocephaly (megalocephaly), defined as greater than or equal to the 97th percentile, 58 cm in an adult woman, or 60 cm in an adult man.≥97th percentile; 58 cm in adult women; 60 cm in adult men
  13. Macular pigmentation of the glans penis.
  14. Mucocutaneous lesions, three or more, with clinical documentation.three or more
  15. Renal cell carcinoma.
  16. Testicular lipomatosis.
  17. Thyroid cancer or thyroid structural lesions, such as adenoma or multinodular goiter.
  18. Vascular anomalies, including multiple intracranial developmental venous anomalies.