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Medical Policy Laboratory Testing Investigational Services Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 165 BCBSA Reference Number: 2.04.159 (For Plan internal use only) NCD/LCD: N/A Related Policies
• 029 Molecular Testing in the Management of Pulmonary Nodules prn.pdf • 163 Maternal Serum Biomarkers for Prediction of Adverse Obstetric Outcomes.pdf • 283 Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease prn.pdf • 530 ST2 Assay for Chronic Heart Failure.pdf • 555 Identification of Microorganisms Using Nucleic Acid Probe prn.pdf • 581 Evaluation of Biomarkers for Alzheimer Disease.pdf • 677 Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis prn.pdf • 702 Serum Biomarker Panel Testing for Systemic Lupus Erythematosus and Other Connective Tissue Diseases prn.pdf • 921 Noninvasive Techniques for the Evaluation and Monitoring of Patients With Chronic Liver Disease prn.pdf • 045 Pathogen Panel Testing.pdf Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

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.

Policy Guidelines Test Name Laboratory PLA code Polygenic Risk Score Many N/A Prometheus® Celiac PLUS Prometheus Laboratories No specific code Prometheus® Crohn's Prognostic Prometheus Laboratories No specific code

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DNA Methylation Pathway Profile Mosaic Diagnostics (formerly Great Plains Laboratory) No specific code

Prometheus® IBD sgi Diagnostic®

Prometheus Laboratories No specific code

know error® Strand Diagnostics No specific code

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

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service.

CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The following CPT codes are considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: CPT Codes CPT codes:

Code Description 0112U Infectious agent detection and identification, targeted sequence analysis (16S and 18S rRNA genes) with drug-resistance gene 0365U Oncology (bladder), 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA), by immunoassays, urine, diagnostic algorithm, including patient's age, race, and gender, reported as a probability of harboring urothelial cancer 0366U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, algorithm reported as a probability of recurrent bladder cancer 0367U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, diagnostic algorithm reported as a risk score for probability of rapid recurrence of recurrent or persistent cancer following transurethral resection

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0376U Oncology (prostate cancer), image analysis of at least 128 histologic features and clinical factors, prognostic algorithm determining the risk of distant metastases, and prostate cancer-specific mortality, includes predictive algorithm to androgen deprivation- therapy response, if appropriate 0384U Nephrology (chronic kidney disease), carboxymethyllysine, methylglyoxal hydroimidazolone, and carboxyethyl lysine by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and HbA1c and estimated glomerular filtration rate (GFR), with risk score reported for predictive progression to high-stage kidney disease 0385U Nephrology (chronic kidney disease), apolipoprotein A4 (ApoA4), CD5 antigen-like (CD5L), and insulin-like growth factor binding protein 3 (IGFBP3) by enzyme-linked immunoassay (ELISA), plasma, algorithm combining results with HDL, estimated glomerular filtration rate (GFR) and clinical data reported as a risk score for developing diabetic kidney disease. 0386U Gastroenterology (Barrett's esophagus), P16, RUNX3, HPP1, and FBN1 methylation analysis, prognostic and predictive algorithm reported as a risk score for progression to high-grade dysplasia or esophageal cancer
0406U Oncology (lung), flow cytometry, sputum, 5 markers (meso-tetra [4-carboxyphenyl] porphyrin [TCPP], CD206, CD66b, CD3, CD19), algorithm reported as likelihood of lung cancer 0415U Cardiovascular disease (acute coronary syndrome [ACS]), IL-16, FAS, FASLigand, HGF, CTACK, EOTAXIN, and MCP-3 by immunoassay combined with age, sex, family history, and personal history of diabetes, blood, algorithm reported as a 5-year (deleted risk) score for ACS 0579U Nephrology (diabetic chronic kidney disease), enzyme-linked immunosorbent assay (ELISA) of apolipoprotein A4 (APOA4), CD5 antigen-like (CD5L) combined with estimated glomerular filtration rate (GFR), age, plasma, algorithm reported as a risk score for kidney function decline 0616U Neurology (dementia), DNA methylation analysis of more than 30,000 sites, whole blood, algorithm reported as positive or negative risk 0617U Cardiovascular (atherosclerotic cardiovascular disease [ASCVD]), DNA methylation analysis of more than 20,000 sites, whole blood, algorithm reported as positive or negative risk 0618U Psychiatry (bipolar disorder), DNA methylation analysis of more than 10,000 sites, whole blood, algorithm reported as positive or negative risk 0619U Pulmonary (chronic obstructive pulmonary disease [COPD]), DNA methylation analysis of more than 18,000 sites, whole blood, algorithm reported as positive or negative risk 0620U Oncology (hepatocellular carcinoma), DNA methylation analysis of more than 5,000 sites, whole blood, algorithm reported as positive or negative risk 0621U Infectious disease (Lyme borreliosis), DNA methylation analysis of more than 10,000 sites, whole blood, algorithm reported as positive or negative risk 0622U Psychiatry (major depressive disorder), DNA methylation analysis of more than 20,000 sites, whole blood, algorithm reported as positive or negative risk 0623U Autoimmune (multiple sclerosis), DNA methylation analysis of more than 5,000 sites, whole blood, algorithm reported as positive or negative risk 0624U Hepatology (nonalcoholic steatohepatitis [NASH]), DNA methylation analysis of 5,000 sites, whole blood, algorithm reported as positive or negative risk 0625U Endocrinology (osteoporosis), DNA methylation analysis of more than 5,000 sites, whole blood, algorithm reported as positive or negative risk 0626U Neurology (Parkinson disease), DNA methylation analysis of more than 20,000 sites, whole blood, algorithm reported as positive or negative risk 0627U Psychiatry (schizophrenia), DNA methylation analysis of more than 15,000 sites, whole blood, algorithm reported as positive or negative risk

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0629U Infectious disease (tuberculosis), DNA, analysis of 1 target by PCR with clustered regularly interspaced short palindromic repeat (CRISPR)-based probe detection, plasma or serum, qualitative report as detected or not detected Description 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.

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. 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.

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.

Policy History Date Action 4/2026 Clarified coding information. 12/2025 Annual policy review. Policy updated with literature review through September 06, 2025; references added. Editorial refinements were implemented. Policy statement unchanged. 10/2025 Clarified coding information. 7/2025 Removed PLA codes 0373U and 0374. Effective 7/2025. 12/2024 Annual policy review. Policy updated with literature review through September 30, 2024; references added. Description for CPT code 0377U corrected in Policy Guidelines. Guidelines updated. Policy statement unchanged. 12/2023 Annual policy review. Policy updated with literature review through September 25,

2023. Policy statement unchanged.

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▪ Codes 0376U, 0384U, 0385U, ongoing investigational were transferred from MP

400 Non-covered services list to MP #165.

▪ Codes 0368U, 0380U, 0405U, 0410U are managed by Carelon Genetic Testing program. Prior authorization is required through Carelon.

These tests are managed by Carelon Genetic Testing program. Prior authorization is required through Carelon. ▪ Prometheus® Celiac PLUS
▪ DNA Methylation Pathway Profile ▪ know error® 10/2023 Coding information clarified. 8/2023 New medical policy describing ongoing investigational indications. Effective 8/2023.
▪ These investigational codes: 0112U; 0365U, 0366U, 0367U were transferred from MP #400 Non-covered services list to MP #165. ▪ Codes 0355U; 0362U are managed by Carelon Genetic Testing program. Prior authorization is required through Carelon.
Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use review.
Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines 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 6, 2025.
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 6, 2025.
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