Medical Policy

Policy Num:      11.003.141
Policy Name:    Laboratory Testing Investigational Services
Policy ID:          [11.003.141] [Ac / B / M- / P-] [2.04.159]

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

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11.001.007 - Identification of Microorganisms Using Nucleic Acid Probes
11.003.079- Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis
11.003.090- Gene Expression Profiling for Uveal Melanoma
11.003.096 - Miscellaneous Genetic and Molecular Diagnostic Tests
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11.003.040 - Genetic Testing for Alzheimer Disease
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11.003.034 - Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
11.003.035 - Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer
11.001.009 - Noninvasive Techniques for the Evaluation and Monitoring of Patients With Chronic Liver Disease
11.003.047- Gene Expression-Based Assays for Cancers of Unknown Primary
11.003.015 - Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer
11.003.098- Use of Common Genetic Variants (Single Nucleotide Variants) to Predict Risk of Nonfamilial Breast Cancer
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11.003.062 - General Approach to Genetic Testing
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11.003.064- Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
11.003.105 - Microarray-Based Gene Expression Profile Testing for Multiple Myeloma Risk Stratification 

11.001.013 - Urinary Biomarkers for Cancer Screening, Diagnosis, and Surveillance 

11.001.038 - Multitarget Polymerase Chain Reaction Testing for Diagnosis of Bacterial Vaginosis

11.003.003 - Multimarker Serum Testing Related to Ovarian Cancer

11.001.011 - Serum Biomarker Human Epididymis Protein 4

11.001.037 - Intracellular Micronutrient Analysis

 Laboratory Testing Investigational Services

Summary

Description

There are numerous commercially available genetic and molecular diagnostic, prognostic, and therapeutic tests for individuals with certain diseases or asymptomatic individuals with future risk. This review relates to genetic and molecular diagnostic tests not addressed in a separate review and have not received clearance/approval/de novo classification from the Food and Drug Administration (FDA). If a separate evidence review exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this review is the limited evidence on the clinical utility for the test. As these tests do not have clinical utility, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome and will not be subjected to a full evidence review.

Summary of Evidence

For individuals with various indications for diagnostic, prognostic, therapeutic, or future risk assessment testing who receive the genetic and molecular tests addressed in this review, the evidence on clinical utility is insufficient or non-evaluable. For each test addressed, a brief description is provided for informational purposes. No formal evidence review was conducted. To sufficiently evaluate clinical utility, features of well-defined test, intended use, and clinical management pathway characteristics are summarized. If it is determined that enough evidence has accumulated to reevaluate its potential clinical utility, the test will be removed from this review and addressed separately. The lack of demonstrated clinical utility of these tests is based on the following factors: (1) there is no or extremely limited published data addressing the test; and/or (2) it is unclear where in the clinical pathway the test fits (replacement, triage, add-on); and/or (3) it is unclear how the test leads to changes in management that would improve health outcomes and/or avoiding existing burdensome and invasive testing; and/or (4) thresholds for decision making have not been established; (5) and/or the outcome from the test result does not result in a clinically meaningful improvement relative to the outcomes(s) obtained without the test.

Objective

The objective of this review is to provide a list of diagnostic, prognostic, therapeutic, or future risk assessment genetic or molecular diagnostic tests with insufficient or non-evaluable clinical utility that are otherwise not addressed in a separate evidence review.

Policy statement

All tests listed in this policy are considered investigational as there is insufficient evidence to determine that the technology results in an improvement in the net health outcome (see Policy Guidelines).

Policy Guidelines

Genetic testing is considered investigational when policy criteria is not met, including when there is insufficient evidence to determine that the technology results in an improvement in the net health outcome. The following tests listed in the table below and within the table in the "Codes" section are considered investigational.

Please refer to the list of related evidence reviews for an assessment of other molecular and genetic tests not listed in this policy.

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 to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. American College of Medical Genetics and Genomics and the Association for Molecular Pathology Standards and Guidelines for Variant Classification

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. Some Plans may have state mandates for biomarker 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

This policy applies if there is not a separate evidence review that outlines specific criteria for testing. If a separate evidence review does exist, then the criteria for medical necessity therein supersede the guidelines herein.

This policy addresses laboratory services considered to be investigational. These tests are often available on a clinical basis before the required and necessary evidence base to support clinical validity and utility is established. Because these tests are often proprietary, there may be no independent test evaluation data available in the early stages to support the laboratory's claims regarding test performance and utility. While studies using these tests may generate information that may help elucidate the biologic mechanisms of disease and eventually help design treatments, the tests listed in this policy are currently in a developmental phase, with limited evidence of clinical utility for diagnosis, prognosis, or risk assessment.

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. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments 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 review was created in June 2023 with a search of the PubMed database. The most recent literature update was performed through September 05, 2025.

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.

Laboratory Testing Investigational Services

Clinical Context and Test Purpose

The purpose of various commercially available genetic and molecular diagnostic, prognostic, and therapeutic tests for individuals with relevant indications is to inform a clinical management decision that improves the net health outcome.

No formal evidence review was conducted.

For individuals with various indications for diagnostic, prognostic, therapeutic, or future risk assessment testing who receive the genetic and molecular tests addressed in this review, the evidence on clinical utility is insufficient or non-evaluable. For each test addressed, a brief description is provided for informational purposes. No formal evidence review was conducted. To sufficiently evaluate clinical utility, features of well-defined test, intended use, and clinical management pathway characteristics are summarized. If it is determined that enough evidence has accumulated to reevaluate its potential clinical utility, the test will be removed from this review and addressed separately. The lack of demonstrated clinical utility of these tests is based on the following factors: (1) there is no or extremely limited published data addressing the test; and/or (2) it is unclear where in the clinical pathway the test fits (replacement, triage, add-on); and/or (3) it is unclear how the test leads to changes in management that would improve health outcomes and/or avoiding existing burdensome and invasive testing; and/or (4) thresholds for decision making have not been established; (5) and/or the outcome from the test result does not result in a clinically meaningful improvement relative to the outcomes(s) obtained without the test.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with 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.

American College of Gastroenterology

In 2023, the American College of Gastroenterology published a clinical practice update for the diagnosis and management of celiac disease.^1, A recommendation for genetic testing using a multigene panel test (eg, Celiac PLUS) was not included.

In 2018, the American College of Gastroenterology practice guidelines on Crohn disease state that genetic and routine serologic testing is not indicated to establish the diagnosis of Crohn's disease.^2,

American Urological Association et al

In 2019, the American Urological Association (AUA) published joint guidelines with the Canadian Urological Association (CUA) and the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) on the management of recurrent uncomplicated urinary tract infections in women.^3, Regarding the use of polymerase chain reaction (PCR) and next-generation sequencing (NGS) techniques for the identification of bacterial species, the guideline states that "more evidence is needed before these technologies become incorporated into the guideline, as there is concern that adoption of this technology in the evaluation of lower urinary tract symptoms may lead to over treatment with antibiotics." In 2022, the guideline was reviewed and validated. In 2025, this guideline was amended but the association still holds the position that "more evidence is needed before these technologies become incorporated into the guideline, as there is concern that adoption of this technology in the evaluation of lower urinary tract symptoms may lead to over treatment with antibiotics."

In 2016, the AUA published joint guidelines with the Society of Urologic Oncology on the diagnosis and treatment of non-muscle invasive bladder cancer.^4, For use of urinary biomarkers after diagnosis, the guidelines state: "a clinician should not use urinary biomarkers in place of cystoscopic evaluation" (Strong Recommendation; Evidence Strength: Grade B); that "in a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance (Expert Opinion); and that "in a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion FISH) and adjudicate equivocal cytology (UroVysion FISH and ImmunoCyt) (Expert Opinion)."

National Comprehensive Cancer Network

National Comprehensive Cancer Network clinical practice guidelines on bladder cancer (v.4.2024 ) state the following regarding urine molecular tests for urothelial tumor markers:^5, "Many of these tests have a better sensitivity for detecting bladder cancer than urinary cytology, but specificity is lower. Considering this, evaluation of urinary urothelial tumor markers may be considered during surveillance of high-risk [non-muscle invasive bladder cancer (NMIBC)]. However, it remains unclear whether these tests offer additional useful information for detection and management of non-muscle invasive bladder tumors. Therefore, the panel considers this to be a category 2B recommendation."

NCCN clinical practice guidelines on colon cancer (v.5.2024 ) state that "it has not been established if molecular markers (other than MSI-H/dMMR) are useful in treatment determination (predictive markers) and prognosis."^6,

National Human Genome Research Institute et al

In 2021, the National Human Genome Research Institute's ClinGen Complex Disease Working Group updated the Genetic Risk Prediction (GRIPS) Reporting Statement in collaboration with the Polygenic Score (PGS) Catalog.^7, The 22-item reporting framework developed to define the minimal information needed to interpret and evaluate polygenic risk scores is summarized in Table 1.

Table 1. Polygenic Risk Score Reporting Statement

  PRS: polygenic risk score.

U.S. Preventive Services Task Force Recommendations

Not applicable.

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

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

References

1. Singh S, Ananthakrishnan AN, Nguyen NH, et al. AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis. Gastroenterology. Mar 2023; 164(3): 344-372. PMID 36822736
2. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. Apr 2018; 113(4): 481-517. PMID 29610508
3. Anger J, Lee U, Ackerman AL, et al. Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline. J Urol. Aug 2019; 202(2): 282-289. PMID 31042112
4. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. Oct 2016; 196(4): 1021-9. PMID 27317986
5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder Cancer [Version 4.2024]. May 9, 2024; https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed September 27, 2024.
6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Colon Cancer [Version 5.2024]. August 22, 2024; https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed September 24, 2024.
7. Wand H, Lambert SA, Tamburro C, et al. Improving reporting standards for polygenic scores in risk prediction studies. Nature. Mar 2021; 591(7849): 211-219. PMID 33692554

Codes

Policy History