RET Proto-Oncogene Testing
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This policy governs medical necessity and coverage criteria for germline RET gene testing (point mutation sequencing) primarily for evaluation of inherited medullary thyroid carcinoma/MEN2 and related indications for Aetna members.
No material clinical or coverage changes in this revision.
Coverage and Medical Necessity Criteria
inv-01: Medically Necessary Indications — Covered when ANY of the following high-risk criteria are met:
Covered when ANY of the following high-risk criteria are met:
Sequencing of the RET gene may be considered.
inv-02: Diagnostic testing in apparent sporadic MTC
inv-03: Germline testing frequency and definition in SPP
Evidence and considerations for germline testing in pheochromocytoma/paraganglioma
From systematic review inclusion criteria.
Tests for germline point mutations in the RET gene are considered experimental and investigational (not covered) for indications other than those specifically listed as medically necessary in this policy. The policy explicitly cites non-small cell lung cancer (NSCLC) as an example of an excluded indication and states that effectiveness for other uses has not been established.
A systematic review of germline testing in apparently sporadic pheochromocytoma/paraganglioma (SPP) found an overall germline mutation frequency of about 11–13%. The review tested for multiple genes including RET but found the most common mutations were in SDHB. The authors noted there were limited outcome data, concluding that the value (benefit vs harm) of germline testing in SPP patients and their family members is unknown because the balance of potential benefits and harms remains unclear.
RET germline testing is not medically necessary / considered experimental and investigational for indications outside the policy’s listed high‑risk criteria. The policy specifically identifies routine RET testing in non‑small cell lung cancer as an example of a non‑covered use and indicates testing for other unlisted clinical scenarios lacks established effectiveness.
Specific Indications Covered
inv-23: First-degree relative with MTC — coverage criteria node
Meets one of the high-risk criteria for germline RET testing.
inv-24: First- or second-degree relative with known germline RET mutation (test for specific familial mutation)
Second-degree relatives include aunt, uncle, grandparent, grandchild, niece, nephew, or half-sibling.
inv-25: Personal history of listed conditions (C-cell hyperplasia; two or more endocrine tumors; Hirschsprung disease; MTC; paraganglioma; parathyroid carcinoma; pheochromocytoma)
Presence of any one of these conditions meets a high-risk criterion for germline RET testing.
inv-26: Diagnostic germline testing for members with apparently sporadic MTC
Used to distinguish sporadic versus familial disease; sequencing of the RET gene may be considered.
inv-27: Hereditary MTC, MEN2 syndromes, and evaluation in patients with pheochromocytoma/paraganglioma where germline mutation testing is considered.
RET testing is commonly used for risk evaluation and to guide prophylactic thyroidectomy in MEN2 families; in pheochromocytoma/paraganglioma, the value of testing in apparently sporadic cases is uncertain but germline mutations have been reported (approximately 11–13% overall in reviewed studies).
Billing Codes and Status
| S3840 | DNA analysis for germline mutations of the RET proto-oncogene for susceptibility to multiple endocrine neoplasia type 2 |
| C73 | Malignant neoplasm of thyroid |
| C74 | Malignant neoplasm of other endocrine glands |
| E07.0 | Hypersecretion of calcitonin |
| Q43.1 | Hirschsprung's disease |
| Z80.8 | Family history of malignant neoplasm of other organs or systems [thyroid cancer] |
| C34.00-C34.92 | Malignant neoplasm of bronchus and lung [non-small cell lung cancer] |
| C75.5 | Malignant neoplasm of aortic body and other paraganglia |
| D35.6 | Benign neoplasm of aortic body and other paraganglia |
| D44.7 | Neoplasm of uncertain behavior of aortic body and other paraganglia |
Provider Responsibilities and Authorization
Prior authorization required for RET testing billed with specified CPT/HCPCS codes
Prior authorization is required when billing molecular pathology CPT codes 81404-81406, molecular cytogenetics code 88271, or the RET-specific HCPCS code S3840; coverage is allowed only if the policy's selection criteria are met.
Policy history provided; no other mandatory prior-authorization process specified
Policy history and review dates are listed (effective 03/18/1999; last review 05/08/2023; next review 03/14/2024), but no additional mandatory prior-authorization process or codes beyond those above are specified in these excerpts.
- Effective: 03/18/1999
- Last Review: 05/08/2023
- Next Review: 03/14/2024
Incorporate genetic counseling into testing and management
Genetic counseling is referenced as part of the testing and management pathway and should be integrated into clinical decision-making surrounding RET testing and subsequent interventions.
- Pre-test and post-test counseling are implied before family members undergo prophylactic surgery.
- Guidelines and recommendations about genetic cancer risk assessment and counseling are referenced.
No step therapy requirements
No step therapy requirements are described in the policy excerpts.
Document clinical justification that member meets a listed high‑risk indication
Clinical documentation must demonstrate that the member meets one of the policy's high‑risk criteria (first‑degree relative with MTC; first‑ or second‑degree relative with a known RET mutation; or personal history of C‑cell hyperplasia, two or more endocrine tumors, Hirschsprung disease, MTC, paraganglioma, parathyroid carcinoma, or pheochromocytoma).
- Evidence that member meets any one of the listed high‑risk indications.
- Sequencing of the RET gene may be considered per testing strategy.
Include indication, family history, and sporadic‑tumor classification in documentation
Clinical records should include the indication for testing (for example, medullary thyroid carcinoma, MEN2, pheochromocytoma/paraganglioma), relevant family history, and whether the tumor is classified as sporadic per the policy's definition.
- Indication (e.g., MTC, MEN2, pheochromocytoma/paraganglioma).
- Family history details (first- or second‑degree relatives, known familial RET mutation).
- For pheochromocytoma/paraganglioma, documentation whether tumor meets SPP definition: absence of family history, absence of syndromic features, absence of bilateral disease, and absence of metastatic disease.
Coverage limited to specified medically necessary indications; other uses are investigational
Testing for germline RET point mutations is considered experimental and investigational (not covered) for indications other than the policy's listed medically necessary indications (example: non‑small cell lung cancer).
- Do not bill/seek coverage for RET germline point‑mutation testing for indications outside the high‑risk list (e.g., routine testing in NSCLC) without documentation meeting policy criteria.
No additional authorization/denial procedures specified in excerpts
The excerpts do not specify explicit authorization or denial procedures or stepwise prior‑authorization steps beyond the code-based prior authorization requirement.
Refer for genetic counseling prior to management decisions (e.g., prophylactic thyroidectomy)
Genetic counseling is referenced as part of the process before family members who test positive undergo prophylactic surgery and should be part of care planning.
- Counseling context is cited in background and referenced guidelines.
Follow cited guideline recommendations for genetic risk assessment and counseling
Guidelines and counseling recommendations are cited; incorporate guideline‑based genetic cancer risk assessment and counseling when ordering and interpreting RET testing.
- References include ATA guidelines and National Society of Genetic Counselors recommendations.
Order testing as part of clinical/genetic management pathway
Order RET germline testing in the context of genetic counseling and clinical management decisions (for example, to inform consideration of prophylactic thyroidectomy for mutation‑positive individuals).
- Testing is intended to guide clinical management in hereditary endocrine/neoplasia syndromes.
No specified ordering‑provider restrictions in policy excerpts
No explicit restrictions on which provider specialty may order testing are specified in these excerpts.
Member Eligibility and Scope
No additional eligibility requirement nodes were specified for this policy beyond the listed medical‑necessity criteria and documentation expectations; eligibility is determined by meeting one of the high‑risk indications described elsewhere in the policy.
There are no separate top‑level eligibility requirement items beyond the coverage criteria. Clinical documentation must demonstrate that the member satisfies one of the policy’s high‑risk indications to support testing.
The policy does not specify additional standalone eligibility rules; coverage is contingent on meeting the enumerated medically necessary indications and providing the required clinical justification.
Key Definitions
Clinical and Scientific Background
Multiple endocrine neoplasia type 2 (MEN2) — including MEN2A, MEN2B and familial medullary thyroid carcinoma (FMTC) — is caused by germline RET mutations and predisposes individuals to medullary thyroid carcinoma (MTC) and other endocrine tumors. Germline RET testing can identify at‑risk individuals, inform risk‑reducing management such as prophylactic thyroidectomy, and help distinguish familial from sporadic MTC; sequencing of the RET gene is the principal testing strategy referenced in the policy.
Services Considered Not Medically Necessary / Not Covered
Germline RET testing is not covered for clinical indications outside the policy’s defined medically necessary list. The policy states that testing for germline RET point mutations is considered experimental and investigational and thus not covered for other uses, explicitly listing non‑small cell lung cancer (NSCLC) as an example of a non‑covered indication.
A systematic review addressing germline testing in apparently sporadic pheochromocytoma/paraganglioma found that while germline mutations were identified in about 11–13% of cases, little outcome data were available to assess clinical benefit. The reviewers therefore concluded the value of germline testing in SPP patients and their families is unknown, given the uncertain balance of benefits and harms.
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