Miscellaneous Genetic and Molecular Diagnostic Tests

POLICY NUMBER

A.2.04.121

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 policy evaluates miscellaneous genetic and molecular diagnostic tests not addressed in a separate review. If a separate policy exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this policy is the limited evidence on the clinical validity for the test. As a result, these tests do not have clinical utility, and the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Tests Addressed in This Medical Policy

The table below lists tests assessed in this policy. Three types of tests are related to testing of an affected (symptomatic) individual's germline to benefit the individual (excluding reproductive testing): diagnostic testing, therapeutic testing, and prognostic testing. The fourth type of test reviewed is testing of an asymptomatic individual to determine future risk of disease.

Genetic and Molecular Diagnostic Tests Assessed In This Medical Policy

Dxcs: Diagnostics; Gxcs: Genetics.ª No therapeutic tests have been identified for this policy.

Diagnostic Tests

Multiple Conditions

Single nucleotide variants (SNVs) are the most common type of genetic variation, and each SNV represents a difference in a single nucleotide in the DNA sequence. Most commonly, SNVs are found in the DNA between genes and can act as biologic markers of genes and disease association. When SNVs occur within a gene or a gene regulatory region, they can play a more direct role in disease by affecting the gene's function. Single nucleotide variants may predict an individual's response to certain drugs, susceptibility to environmental factors, and the risk of developing certain diseases.

DNA specimen provenance assays can be used to confirm that tissue specimens are correctly matched to the patient of origin. Specimen provenance errors may occur in up to 1% to 2% of pathology tissue specimens, and have serious negative implications for patient care if the error is not corrected. Analysis of DNA microsatellites from tissue specimens can be performed by analyzing long tandem repeats (LTR) and comparing the LTRs of the tissue specimen with LTRs from a patient sample.

Test Description: DNA Methylation Pathway Profile

The DNA Methylation Pathway Profile (Mosaic Diagnostics) analyzes SNVs associated with certain biochemical processes, including methionine metabolism, detoxification, hormone imbalances, and vitamin D function. Intended uses for the test include clarification of a diagnosis suggested by other testing and as an indication for supplements and diet modifications.

Test Description: know error DNA Specimen Provenance Assay

The know error system (Strand Diagnostics) compares the LTRs of tissue samples with LTRs from a buccal swab of the patient. The intended use of the test is to confirm tissue of origin and avoid specimen provenance errors due to switching of patient samples, mislabeling, or sample contamination.

Celiac Disease

Previously called sprue, celiac sprue, gluten-sensitive enteropathy, gluten intolerance, nontropical sprue, or idiopathic steatorrhea, celiac disease is an immune-based reaction to gluten (water-insoluble proteins in wheat, barley, rye) that primarily affects the small intestine. Celiac disease occurs almost exclusively in patients who carry at least 1 human leukocyte antigen DQ2 or DQ8; the negative predictive value of having neither allele exceeds 98%. Serum antibodies to tissue transglutaminase, endomysium, and deamidated gliadin peptide support a diagnosis of celiac disease, but diagnostic confirmation requires duodenal biopsy taken when patients are on a gluten-containing diet.

Test Description: Celiac PLUS

Celiac PLUS (Prometheus Laboratories) is a panel of 2 genetic and 5 serologic markers associated with celiac disease. Per the manufacturer, Celiac PLUS is a diagnostic test that also stratifies the future risk of celiac disease. Genetic markers (human leukocyte antigen DQ2 and DQ8) are considered predictive of the risk of developing celiac disease; serologic markers (immunoglobulin A [IgA] anti-tissue transglutaminase antibody, IgA anti-endomysial antibodies, IgA anti-deamidated gliadin peptide antibodies, IgG anti-deamidated gliadin peptide, and total IgA) are considered diagnostic for celiac disease. Celiac PLUS is intended for patients at risk for the disease (eg, with an affected first-degree relative) or with symptoms suggestive of the disease.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder that affects 10% to 20% of the general population in the U. S. and worldwide. Symptoms include abdominal pain and/or bloating associated with disordered bowel habit (constipation, diarrhea, or both). Pathophysiology is poorly understood but may be related to chronic low-grade mucosal inflammation and disturbances in GI flora. Recommended treatments include dietary restriction and pharmacologic symptom control. As living microorganisms that promote health when administered to a host in therapeutic doses, probiotics are being investigated as a treatment for IBS. Several systematic reviews of randomized controlled trials have found evidence to support efficacy, but results from recent randomized controlled trials have been mixed. This discrepancy may be due in part to the differential effects of different probiotic strains and doses.

Test Description: GI Effects Comprehensive Stool Profile

The GI Effects Comprehensive Stool Profile (Genova Diagnostics) is a multianalyte stool assay. The test uses polymerase chain reaction (PCR) to quantify 26 commensal gut bacteria and standard biochemical and culture methods to measure levels of other stool components (eg, lipids, fecal occult blood) and potential pathogens (ova and parasites, opportunistic bacteria, yeast). The test is purported to optimize management of gut health and to differentiate IBS from inflammatory bowel disease (IBD).

Inflammatory Bowel Disease

Inflammatory bowel disease is an autoimmune condition characterized by inflammation of the bowel wall and has clinical symptoms of abdominal pain, diarrhea, and associated symptoms. Crohn disease (CD) and ulcerative colitis are the 2 main entities under the category of IBD. The diagnosis is typically made by endoscopy or colonoscopy with biopsy and histologic analysis. This requires a semi-invasive procedure; as a result, a blood test to diagnose IBD could avoid the need for the procedures.

Test Description: IBD sgi Diagnostic

IBD sgi Diagnostic (Prometheus Laboratories) is a panel of 17 serologic (n=8), genetic (n=4), and inflammatory (n=5) biomarkers. A proprietary algorithm produces an IBD score; results are reported as consistent with IBD (consistent with ulcerative colitis, consistent with CD, or inconclusive for ulcerative colitis vs. CD) or not consistent with IBD. The test is intended for use in patients with clinical suspicion of IBD.

Crohn's Disease

Test Description: Monitr Crohn’s Disease Test

The Monitr Crohn’s Disease Test (Prometheus Laboratories) is a laboratory-developed test that evaluates multiple markers of mucosal damage and repair processes, regardless of disease location.  It applies a proprietary algorithm to 13 biomarkers to produce a quantitative Endoscopic Healing Index (EHI) Score—ranging from 0 to 100—to aid in distinguishing endoscopic remission from active disease in adult CD patients.

Therapeutic Tests

Previously reviewed therapeutic tests are no longer commercially available; no commercially available therapeutic test is reviewed in this policy.

Prognostic Tests

Crohn Disease

Recent studies have identified serologic and genetic correlates of aggressive CD that is characterized by fistula formation, fibrostenosis, and the need for surgical intervention. Prometheus has developed a blood test that aims to identify patients with CD who are likely to experience an aggressive disease course.

Test Description: Crohn's Prognostic

Crohn's Prognostic (Prometheus Laboratories) is a panel of 6 serologic (n=3) and genetic (n=3) biomarkers. Limited information about the test is available on the manufacturer's website.

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. Genetic tests evaluated in this policy are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under 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 these tests.

The ImmunoGenomic Profile (Genova Diagnostics) was a buccal swab test that evaluates SNVs in 6 genes associated with immune function and inflammation: interleukin (IL)-10, IL-13, IL-1b, IL-4, IL-6, and tumor necrosis factor α. The test was intended to uncover potential genetic susceptibility to: asthma, autoimmune disorders, certain cancers, allergy, infectious diseases, bone inflammation, arthritis, inflammatory bowel disease, heart disease, osteopenia, and Helicobacter pylori infection. Due to low testing volume, this test was discontinued in February 2022.

POLICY

All tests listed in this policy are considered investigational and grouped according to the categories of genetic testing outlined in the General Approach to Genetic Testing medical policy:

• Testing of an affected (symptomatic) individual's germline to benefit the individual (excluding reproductive testing)

• Diagnostic testing

• Prognostic testing

• Therapeutic testing

• Testing an asymptomatic individual to determine future risk of disease.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetic testing is considered investigational when BCBSMS criteria are not met, including when there is insufficient evidence to determine that the technology results in an improvement in the net health outcome.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

05/15/2021: New policy added. Approved by Medical Policy Advisory Committee.

08/30/2021: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic testing.

08/09/2022: Policy description updated regarding therapeutic tests. Policy statement unchanged.

11/08/2022: Policy reviewed; no changes.

03/03/2023: Monitr® Crohn’s Disease Test added to policy description.

11/10/2023: Policy description updated regarding genetic and molecular tests. Policy statements unchanged.

12/07/2023: Policy reviewed; no changes.

07/24/2024: Policy reviewed; no changes.

08/16/2024: Policy reviewed; no changes.

04/01/2025: Code Reference section updated to add new CPT code 0548U, effective 04/01/2025.

07/18/2025: Code Reference section updated to add new CPT code 0570U. Effective 07/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.121

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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