Medical Policy

Policy Num:      11.003.062
Policy Name:    General Approach to Genetic Testing
Policy ID:          [11.003.062]  [Ac / B / M+ / P+]  [2.04.91]

Last Review:       January 21, 2025
Next Review:      January 20, 2026
 

Related Policies:

11.003.023 General Approach to Evaluating the Utility of Genetic Panels 

11.003.048 Carrier Testing for Genetic Diseases
11.003.079 Invasive Prenatal (Fetal) Diagnostic Testing
11.003.070 Preimplantation Genetic Testing

General Approach to Genetic Testing

Summary

Commercially available genetic tests can perform a host of functions, such as providing a guided intervention in both symptomatic or asymptomatic people, identifying people at risk for future disorders, predicting the prognosis of a diagnosed disease, and predicting the appropriate treatment response.

The conceptual framework provided herein offers an outline for evaluating the utility of genetic tests, by classifying the types of genetic tests into clinically relevant categories and developing criteria that can be used for evaluating tests in each category.

This conceptual framework addresses genetic testing in nonreproductive settings. Genetic testing in reproductive settings is addressed separately (eg, evidence reviews 2.04.107, 2.04.116, 4.02.05). For categories of genetic testing for which the benefit of testing is the individual, criteria for medical necessity apply. When the benefit of testing is not for the individual, but for a family member, medical necessity criteria may not apply, and the criteria are developed for clinical utility.

Objective

The objective of this review is to outline the conceptual framework used by BCBSA to assess the clinical utility of genetic tests.

Policy Statements

Genetic testing classified in one of the categories below may be considered medically necessary when all criteria are met for each category, as outlined in the Rationale section:

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

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

2.     Testing cancer cells of an affected individual to benefit the individual

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

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

Genetic testing that does not meet the criteria for a specific category is considered investigational or not medically necessary, according to the standard definitions used for these terms (see Policy Guidelines section).

Policy Guidelines

For the following category of testing, the benefit of testing is for a family member rather than the individual being tested. In this category, the criteria developed are for clinical utility.

•         Testing of an affected individual's germline to benefit family member(s).

Genetic testing is considered not medically necessary when:

•         testing is not considered standard of care, such as when the clinical diagnosis can be made without the use of a genetic test;

•         testing is not clinically appropriate for the patient's condition (eg, when it would not change diagnosis and/or management). Other situations where testing is not clinically appropriate include, but are not limited to:

o    testing performed entirely for nonmedical (eg, social) reasons;

o    testing not expected to provide a definitive diagnosis that would obviate the need for further testing.

•         testing is performed primarily for the convenience of the patient, physician, or other health care provider;

•         testing would result in outcomes that are equivalent to outcomes using an alternative strategy, and the genetic test is more costly.

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-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

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

If the specific analyte is listed in codes 81200-81355 or 81400-81408, that CPT code would be reported. If the specific analyte is not listed in the more specific CPT codes, unlisted code 81479 would be reported.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic 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

The purpose of this conceptual framework is to assist evaluation of the utility of genetic tests. In providing a framework for evaluating genetic tests, this review will not determine the clinical utility of genetic testing for specific disorders. Rather, it provides guidelines that can be applied to a wide range of tests.

This conceptual framework applies only if there is not a separate evidence review that outlines specific criteria for testing. If a separate review exists, then the criteria for medical necessity in that evidence review supersede the guidelines herein.

This conceptual framework does not include cytogenetic testing (karyotyping), biochemical testing, or molecular testing for infectious disease.

This conceptual framework also does not address reproductive genetic testing. There are separate evidence reviews for genetic testing in the reproductive setting, addressing, eg, carrier testing for genetic diseases (2.04.107), invasive prenatal (fetal) diagnostic testing (2.04.116), and preimplantation genetic testing (4.02.05).

The following categories of genetic testing are addressed herein (see Appendix 1):

1.     Testing of an affected (symptomatic) individual's germline to benefit the individual

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

2.     Testing cancer cells of an affected individual to benefit the individual

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

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

4.     Testing of an affected individual's germline to benefit family members.

BCBSA genetic testing category 5 (Reproductive testing) is not addressed herein.

Definitions

Genetic Testing

Genetic testing involves the analysis of chromosomes, DNA, RNA, genes, or gene products to detect inherited (germline) or noninherited (somatic) genetic variants related to disease or health.

Carrier Testing

A carrier of a genetic disorder has 1 abnormal allele for a disorder. When associated with an autosomal recessive or X-linked disorder, carriers of the causative variant are typically unaffected. When associated with an autosomal dominant disorder, the person has 1 normal copy of the gene and 1 mutated copy of the gene; such a person may be affected with the disorder, may be unaffected but at high risk of developing the disease later in life, or may remain unaffected because of the sex-limited nature of the disease.

Carrier testing may be offered to people: (a) who have family members with a genetic condition; (b) who have family members who are identified carriers; and (c) who are members of ethnic or racial groups known to have a higher carrier rate for a particular condition.

Germline Variants

Germline variants are present in the DNA of every cell of the body, from the moment of conception. They include cells in the gonads (testes or ova) and could, therefore, be passed on to offspring.

Somatic Variants

Somatic variations occur with the passage of time and are restricted to a specific cell or cells derived from it. If these variants are limited to cells that are not in the gonads, they will not be passed on to offspring.

Pharmacogenomics

Pharmacogenomics studies how a person's genetic makeup affects his or her body's response to drugs.

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. Most genetic tests are lab tests available under the auspices 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 conceptual framework was created in May 2013 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 7, 2017.

General Principles of Genetic Tests

A test should be cleared or approved by the U.S. Food and Drug Administration or performed in a Clinical Laboratory Improvement Amendments-certified laboratory.

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 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 following rubric outlines the steps in assessing a medical test. The first step is to formulate the clinical context and purpose of the test. Then the evidence is reviewed to determine whether the test is technically reliable, clinically valid, and clinically useful. However, as noted below, technical reliability is outside the scope of evidence reviews.^1,2,

Population Reference No. 1 

Types of Genetic Tests Addressed in This conceptual framework

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

a.     Diagnostic: To confirm or exclude genetic or heritable variants in a symptomatic person. This refers to a molecular diagnosis supported by the presence of a known pathogenic variant. For genetic testing, a symptomatic person is defined as an individual with a clinical phenotype correlated with a known pathogenic variant.

b.     Prognostic: To determine or refine estimates of disease natural history or recurrence in patients already diagnosed with disease in order to predict natural disease course (eg, aggressiveness, recurrence, risk of death). This type of testing may use gene expression of affected tissue to predict the course of disease (eg, testing breast cancer tissue with Oncotype DX).

c.     Therapeutic: To determine that a particular therapeutic intervention is effective (or ineffective) for an individual. To determine the probability of favorable or adverse response to medications. To detect genetic variants that alter risk of treatment response, adverse events, drug metabolism, drug effectiveness, etc. (eg, cytochrome P450 testing). To detect genetic variants that adversely affect response to exposures in the environment that are ordinarily tolerated (eg, G6PD deficiency, genetic disorders of immune function, aminoacidopathies).

2.     Testing cancer cells of an affected individual to benefit the individual

a.     Diagnostic: To determine the origin of a cancer or to determine a clinically relevant subgroup into which a cancer is classified.

b.     Prognostic: To determine the risk of progression, recurrence, or mortality for a cancer that is already diagnosed.

c.     Therapeutic: To determine the likelihood that a patient will respond to a targeted cancer therapy that is based on the presence or absence of a specific variant.

Population Reference No. 2 

3.     Testing an asymptomatic individual to determine future risk of disease. To detect genetic variants associated with disorders that appear after birth, usually later in life. Such testing is intended for individuals with a family history of a genetic disorder, but who themselves have no features of the disorder, at the time of testing, in order to determine their risk for developing the disorder.

4.     Testing of an affected individual's germline to benefit family member(s). To focus and direct family testing of asymptomatic relatives, by testing an individual with known disease but in whom the presence or absence of a pathogenic variant has not been determined.

Medical Necessity Criteria

The criteria listed below for medical necessity represent minimum criteria that must be met in each category to conclude that a test is medically necessary. Alternative approaches to grouping these factors are presented in Appendix 2. The tables in Appendix 2 list all factors considered for clinical utility, and the figures in Appendix 2 group the factors into a branching logic schematic that facilitates a decision whether the test does or does not meet clinical utility.

Genetic testing is considered medically necessary for a genetic or heritable disorder when the following are met.

For ALL genetic testing, the condition being tested for must have either:

•         Reduced life expectancy OR

•         At least moderate-to-severe morbidity.^3,

For the specific categories of testing, the following criteria must also be met:

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

a.     Diagnostic

                           i.   An association between the marker and the disorder has been established AND

                          ii.   Symptoms of the disease are present AND

                         iii.   A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, and standard diagnostic studies/tests AND

                         iv.    The clinical utility of identifying the variant has been established (see Appendix 2):

1)    Leads to changes in clinical management of the condition that improve outcomes OR

2)    Eliminates the need for further clinical workup or invasive testing OR

3)    Leads to discontinuation of interventions that are unnecessary and/or ineffective,

b.     Prognostic

                           i.   An association between the marker and the natural history of the disease has been established AND

                          ii.   Clinical utility of identifying the variant has been established (see Appendix 2):

1)    Provides incremental prognostic information above that of standard testing AND

2)    Reclassifies patients into clinically relevant prognostic categories for which there are different treatment strategies AND

3)    Reclassification leads to changes in management that improve outcomes.

c.     Therapeutic

                           i.   Genetic testing identifies variants of a phenotype/metabolic state that relate to different pharmacokinetics, drug efficacy, or adverse drug reactions AND

                          ii.   Clinical utility of identifying the variant has been established (see Appendix 2):

1)    Leads to initiation of effective medication(s) OR

2)    Leads to discontinuation of medications that are ineffective or harmful OR

3)    Leads to clinical meaningful change in dosing of medication that is likely to improve outcomes.

2.     Testing cancer cells of an affected individual to benefit the individual

a.     Diagnostic

                           i.   Genetic testing can establish the cell origin of a cancer when the origin is uncertain following standard workup AND

                          ii.   Clinical utility of identifying the variant has been established (see Appendix 2):

1)    Start effective treatment OR

2)    Discontinue ineffective or harmful treatment

b.     Prognostic

                           i.   An association between the marker and the natural history of the disease has been established AND

                          ii.   Clinical utility of identifying the variant has been established (see Appendix 2):

1)    Provides incremental prognostic information above that of standard testing AND

2)    Reclassifies patients into clinically relevant prognostic categories for which there are different treatment strategies AND

3)    Reclassification leads to changes in management that improve outcomes.

c.     Therapeutic

                           i.   Association between a variant and treatment response to a particular drug has been established AND

                          ii.   Clinical utility has been established (see Appendix 2):

1)    The patient is a candidate for targeted drug therapy associated with a specific variant AND

2)    There is a clinically meaningful improvement in outcomes when targeted therapy is given for the condition.

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

                           i.   An association between the marker and future disorder has been established AND

                          ii.   Clinical utility has been established (see Appendix 2):

1)    There is a presymptomatic phase for this disorder and interventions or surveillance are available AND

2)    Interventions in the presymptomatic phase are likely to improve outcomes:

a.     Prevent or delay onset of disease OR

b.     Detect disease at an earlier stage during which treatment is more effective OR

c.     Discontinuation of ineffective or unnecessary interventions.

Clinical Utility Criteria

For the following category, focusing on the benefit of testing for another individual, the definition of medical necessity may not apply. When an individual is tested to benefit a family member, and there is no benefit for the individual being tested, eligibility for coverage depends on individual plan benefit language. Individual plans may differ whether benefit structure allows testing of an individual to benefit an unaffected family member.

For these reasons, the following criteria are considered for clinical utility of testing and not for medical necessity.

4.     Testing of an affected individual's germline to benefit family members

                     i.   An association between the genetic variant and clinical disease has been established AND

                    ii.   Family members are available who may be at risk for the disorder AND

                   iii.   The individual tested has a clinical diagnosis of the condition (or represents the family member who is most likely to harbor the pathogenic variant), but genetic testing has not been performed AND

                  iv.    There is a presymptomatic phase for the disorder in which interventions are available AND

                   v.    Interventions in the presymptomatic phase are likely to improve outcomes in one of the following ways:

1)    Prevent or delay onset of disease;

2)    Detect disease at an earlier stage during which treatment is more effective;

3)    Discontinuation of interventions that are ineffective or unneeded.

Limitations of Genetic Testing

•         The testing methods may not detect all variants that may occur in a gene.

•         Genetic testing may identify variants of uncertain significance.

•         Genetic testing may not necessarily determine the clinical outcome.

•         Different genes can cause the same disease (genetic heterogeneity).

•         A variant in a gene may cause different phenotypes (phenotypic heterogeneity).

•         Some disease-causing genes may not yet be identified.

•         Genetic testing is subject to laboratory error.

Summary of Evidence

This conceptual framework addresses genetic testing in nonreproductive settings. Genetic testing in reproductive settings is addressed separately (eg, evidence reviews 2.04.107, 2.04.116, 4.02.05). For categories of genetic testing for which the benefit of testing is the individual, criteria for medical necessity apply. When the benefit of testing is not for the individual, but for a family member, medical necessity criteria may not apply, and the criteria are developed for clinical utility.

Supplemental Information

Practice Guidelines and Position Statements

No guidelines or statements were identified.

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

A search of ClinicalTrials.gov in November 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

References

1. ACMG Board of Directors. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet Med. Jun 2015;17(6):505-507. PMID 25764213

2. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. Jan 2009;11(1):3-14. PMID 18813139

3. Beltran-Sanchez H, Razak F, Subramanian SV. Going beyond the disability-based morbidity definition in the compression of morbidity framework. Glob Health Action. Sep 2014;7:24766. PMID 25261699

Codes

Applicable Modifiers

N/A

Policy History