MEDICAL POLICY

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APPENDIX
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General Approach to Genetic Testing

Number 12.04.91

Effective Date July 14, 2014

Revision Date(s) 07/14/14; 08/12/13

Replaces 2.04.91

Policy

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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:

  • Diagnostic testing
  • Risk assessment
  • Prognostic testing
  • Genetic variants that alter response to treatment or to an environmental factor

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).

Genetic testing is considered not medically necessary when performed entirely for non-medical reasons (e.g., a general interest in genetic test results).

Note: This policy applies only if there is not a separate policy that outlines specific criteria for testing. If a separate policy does exist, then the criteria for medical necessity in that policy supersede the guidelines in this policy. (See Related Policies)

Related Policies

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12.04.92

General Approach to Evaluating the Utility of Genetic Panels

12.04.121

Miscellaneous Genetic and Molecular Diagnostic Tests

Policy Guidelines

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Definitions:

Experimental/Investigational

Genetic testing is considered investigational when the Blue Cross Blue Shield Association Technical Evaluation Center (TEC) criteria are not met, including when there is insufficient evidence to determine whether the technology improves health outcomes.

Any technology that fails to meet ALL of the following TEC criteria is considered to be “Investigational”:

  1. The technology must have final approval from the appropriate governmental regulatory bodies.
  2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
  3. The technology must improve the net health outcome.
  4. The technology must be as beneficial as any established alternatives.
  5. The improvement must be attainable outside the investigational settings.

Not Medically Necessary

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, for example, when it would not change diagnosis and/or management. Other situations where testing is not clinically appropriate include, but are not limited to:
  • Testing is performed entirely for nonmedical (e.g., social) reasons
  • Testing is 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.

Effective in 2013, 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.

Description

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There are numerous commercially available genetic tests, including those used to guide intervention in symptomatic or asymptomatic people, to identify people at risk for future disorders, to predict the prognosis of diagnosed disease and to predict treatment response. This concept policy offers a framework 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.

Background

Purpose

The purpose of this policy is to provide assistance in evaluating the utility of genetic tests. In providing a framework for evaluating genetic tests, this policy will not attempt to determine the clinical utility of genetic testing for specific disorders. Rather, it provides guidelines that can be applied to a wide range of different tests.

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

This policy does not address prenatal testing.

Definitions

Genetic testing: Genetic testing involves the analysis of chromosomes, DNA (deoxyribonucleic acid), RNA (ribonucleic acid), genes or gene products to detect inherited (germline) or non-inherited (somatic) genetic variants related to disease or health.

Carrier testing: A carrier of a genetic disorder has one abnormal allele for a disorder. When associated with an autosomal recessive or X-linked disorder, carriers of the causative mutation are typically unaffected. When associated with an autosomal dominant disorder, the person has one normal and one mutated copy of the gene and may be affected with the disorder, may be unaffected but at high risk of developing the disease later in life, or the carrier 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 mutations: Mutations that are present in the DNA of every cell of the body, present from the moment of conception. These include cells in the gonads (testes or ova) and could therefore be passed on to offspring.

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

Pharmacogenomics: Study of how a person’s genetic makeup affects the body’s response to drugs.

Scope

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Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

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N/A

Rationale

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General principles of genetic tests

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

Peer-reviewed literature on the performance and indications for the test should be available. This evaluation of a genetic test focuses on 3 main principles: 1) analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); 2) clinical validity, (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and 3) clinical utility ( i.e., how results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

Types of genetic tests addressed in this policy

  1. Diagnostic testing for genetic or heritable mutations in a symptomatic person. This refers to a molecular diagnosis defined by the presence of a known pathologic mutation. For the purposes of genetic testing, a symptomatic person is defined as a person with a clinical phenotype that is correlated with a known pathologic mutation.
  2. Risk assessment for genetic and heritable mutations.
  1. Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, usually later in life. These tests can be used in people with a family history of a genetic disorder, but who themselves have no features of the disorder at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer or cardiovascular disease. Presymptomatic testing can determine whether a person will develop a genetic disorder, before any signs or symptoms appear, by determining whether a person has a genetic mutation that may lead to development of the disease.
  2. Carrier testing is performed in a people who may be at risk of passing on a mutation to their children. This type of testing is offered to people who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions .
  1. Prognostic testing of diagnosed disease to predict natural disease course, e.g., aggressiveness, recurrence, risk of death. This type of testing uses gene expression of affected tissue to predict the course of disease. e.g., testing breast cancer tissue with Oncotype Dx.
  2. Genetic variants that alter response to treatment or to an environmental factor
  1. Constitutional (germline) testing to detect genetic variants that alter risk of treatment response, adverse events, drug metabolism, drug effectiveness, etc. e.g., cytochrome p450 testing (Also referred to as pharmacogenomics).
  2. Tissue -specific or tumor testing: to detect mutations that predict response to a certain type of treatment (e.g., ALK mutation in non-small -cell lung cancer to predict response to crizotinib)
  3. Genetic mutations that adversely affect response to exposures in the environment that are ordinarily tolerated, such as G6PD deficiency, genetic disorders of immune function, and aminoacidopathies.

Medical Criteria

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

  1. Diagnostic testing for genetic or heritable mutations of an affected person
  1. An association of the marker with the disorder has been established AND
  2. Symptoms of the disease are present AND
  3. A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, standard diagnostic studies/tests AND
  4. The clinical utility of a diagnosis has been established (see Appendix) for example by demonstrating that a definitive diagnosis will lead to changes in clinical management of the condition, changes in surveillance or changes in reproductive decision making, and the changes will lead to improved health outcomes AND
  5. Establishing the diagnosis by genetic testing will end the clinical work-up for other disorders
  1. Risk assessment
  1. Predictive and presymptomatic:
  • An association of the marker with future disorder has been established AND
  • clinical utility has been established (see Appendix), for example by demonstrating that Testing will lead to improved health outcomes based on prevention or early detection strategies
  1. Carrier testing
  • An association of the marker with the disorder has been established AND
  • The genetic disorder is associated with a potentially severe disability or has a lethal natural history AND
  • the clinical utility has been established (see Appendix), for example by demonstrating that The results of the test will have an impact on family planning
  1. Prognostic testing
  1. An association of the marker with the natural history of the disease has been established AND
  2. Clinical utility of identifying the mutation has been established, for example by demonstrating that it will lead to changes in clinical management of the condition or changes in surveillance
  1. Genetic variants that alter response to treatment or to an environmental factor
  1. Constitutional (germline) testing:
  • Association of the marker with a phenotype/metabolic state that relates to drug efficacy or adverse drug reactions has been established AND
  • clinical utility has been established (see Appendix), for example by demonstrating that The results of the genetic test will impact clinical decision making and will be expected to result in improved clinical outcomes for the patient based on drug selection or dosage
  1. Tissue -specific or tumor testing:
  • Association of a mutation with response to a particular drug has been established AND
  • Clinical utility has been established (see Appendix), for example by demonstrating that The patient is a candidate for targeted drug therapy which is associated with a specific mutation

Genetic Counseling

The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, most or all genetic testing for heritable conditions should be preceded by genetic counseling so that the patient understands whether genetic testing should be performed, or, if it is performed, what the potential impact of the information could be on the patient and on his or her family.

Limitations of Genetic Testing

The testing methods may not detect all of the mutations that may occur in a gene

  • Genetic testing may identify variants of unknown clinical significance
  • Genetic testing may not necessarily determine the clinical outcome
  • Different genes can cause the same disease (genetic heterogeneity)
  • A mutation in a gene may cause different phenotypes (phenotypic heterogeneity)
  • Some disease-causing genes may not be identified as of yet
  • Genetic testing is subject to laboratory error

References

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  1. Available online at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/ Last accessed March, 2014.
  2. Available online at: http://www.nhmrc.gov.au/guidelines/publications/e99 Last accessed March, 2014.
  3. 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 2009; 11(1):3-14.

Coding

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Codes

Number

Description

CPT

81200-81355

Molecular diagnostics, code range

 

81400-81408

Molecular pathology procedure code range

 

81479

Unlisted molecular pathology procedure

Appendix

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APPENDIX 1

APPROACH TO DETERMINING CLINICAL UTILITY FOR GENETIC TESTING

Direct Evidence

If direct evidence is available on the impact of testing on outcomes, this evidence takes precedence. Examples of direct evidence would be:

  • Trial comparing outcomes with use of the test versus outcomes without use of the test
  • Associational study of genetic testing with outcomes

Indirect Evidence

When direct evidence is not available, indirect evidence should be evaluated. Indirect evidence is evidence that addresses one or more components of a chain of evidence, but does not itself connect the intervention with the outcome.

An example of indirect evidence is the accuracy of the genetic test for diagnosing the clinical condition, ie, clinical sensitivity and specificity. If improved accuracy leads to improved diagnosis of the disorder, and if more accurate diagnosis leads to management changes that improve outcomes, then clinical utility has been established.

Many of these disorders are rare, and high-quality evidence on the efficacy of treatment for the disorder is often lacking. This is particularly true for aspects of management such as increased surveillance for complications, ancillary treatments (physical therapy, occupational therapy, etc.), and referrals to specialists. When evidence on outcomes is lacking, a consideration may be given as to whether these aspects of care are considered standard-of-care for that disorder, especially when they are part of guidelines by authoritative bodies.

There are a number of factors that influence the strength of indirect evidence that is needed to determine whether health outcomes are improved. None of these factors are by themselves determinative of whether genetic testing should be performed, but they may be important determinants of the potential clinical utility of testing Some of these considerations are as follows:

  1. Diagnostic testing - Factors impacting the strength of indirect evidence

Disease Characteristics

  • Is life expectancy reduced with this disorder?
  • What is the level of physical and/or psychosocial morbidity (disability) associated with the disorder?
  • Severe morbidity/disability
  • Moderate morbidity/disability
  • Minor or no morbidity/disability

Impact of genetic test on diagnosis

  • Can genetic testing confirm the suspected diagnosis?
  • Can the diagnosis be confirmed by alternate methods without genetic testing?
  • Disorder is defined by the presence of genetic mutation
  • Genetic test is one of several factors contributing to diagnosis
  • Unable to make diagnosis without genetic test in some patients
  • Can genetic testing rule out the disorder?
  • Can genetic testing eliminate the need for further clinical work-up?
  • Is this a disorder in which the diagnosis can be difficult, and the patient may be subjected to long and complicated work-ups?

Impact of genetic test on management

  • Does confirmation of diagnosis by genetic testing lead to improved outcomes?
  • Initiation of effective treatment
  • Discontinuation of ineffective treatment
  • Does confirmation of diagnosis by genetic testing lead to the Initiation of other management changes with uncertain impact on outcomes (referrals to specialists and/or ancillary care, initiate screening, etc.)
  • Does confirmation of diagnosis by genetic testing lead to initiation of other management changes that are considered “standard of care” treatment for disorder

Impact on Health Outcomes

  • Is there a definite improvement in health outcomes with genetic testing? For example:
  • Diagnosis cannot be made without genetic testing, and confirmation of diagnosis leads to initiation of effective treatment
  • Is there a possible, but not definite, improvement in health outcomes with genetic testing? For example:
  • Diagnosis cannot be made without genetic testing, and confirmation of diagnosis leads to management changes with uncertain impact on outcomes
  • Are there significant barriers to research, such as rarity of the disorder?
  • What is the impact of genetic testing on lifestyle factors?
  • Employment/occupational decision making
  • Leisure activities
  • Reproductive decision maker

Appendix Table A. Factors influencing the strength of an indirect chain of evidence on clinical utility – diagnostic testing

Disorder

Disease Characteristics

Impact on Diagnosis

Impact on Management

Impact on Outcomes

 

Shortened LE

Severe morbidity/disability

Moderate morbidity/disability

Minor or no morbidity/disability

Confirms diagnosis

Condition defined by mutation

Confirms diagnosis, o/w

Unable to make clinically

Contributes to ability to make diagnosis

Rules out disorder

Eliminates need for other clinical workup

Initiate effective treatment for disorder

Discontinue ineffective treatment

Initiate other management changes

Provide ‘standard of care’ treatment for disorder

Change in management with improved health outcomes

Change in management with uncertain impact on outcomes

Barriers to research

Impact on lifestyle factors

                                   
                                   

  1. Risk Assessment testing - Factors impacting the strength of indirect evidence

Disease Characteristics

  • Is life expectancy reduced with this disorder?
  • What is the level of physical and/or psychosocial morbidity (disability) associated with the disorder?
  • Severe morbidity/disability
  • Moderate morbidity/disability
  • Minor or no morbidity/disability
  • Is there a presymptomatic phase during which a clinical diagnosis cannot be made?

Impact of genetic test on defining risk of disease

  • Can genetic testing determine the risk of subsequent disease in at least a substantial proportion of the population tested?
  • Is there a known mutation in the family?
  • Is the penetrance of the genetic mutation known?
  • Are there other factors that impact the clinical expression of disease?
  • Impact of genetic test on management
  • Does confirmation of risk lead to interventions that are indicated for this condition in the presymptomatic phase
  • Interventions that prevent or delay disease onset
  • Surveillance for manifestations or complications of disease
  • Does confirmation of risk by a positive genetic test lead to the initiation of other management changes that may or may not lead to improved outcomes (referrals to specialists and/or ancillary care, initiate screening, etc.)
  • Does a negative test confirm a lack of risk for the disease, and does this lead to “turning off” interventions, such as surveillance, that would otherwise be performed?
  • Is it likely that knowledge of mutation status will lead to alterations in reproductive decision making?

Impact on Health Outcomes

  • Is there a definite improvement in health outcomes with genetic testing? For example:
  • risk assessment cannot be made without genetic testing, and confirmation of risk leads to initiation of effective preventive interventions that delay onset of disease
  • Is there a possible, but not definite, improvement in health outcomes with genetic testing? For example:
  • Risk assessment cannot be made without genetic testing, and confirmation of risk leads to management changes with uncertain impact on outcomes
  • Are there significant barriers to research, such as rarity of the disorder?
  • What is the impact of genetic testing on lifestyle factors?
  • Employment/occupational decision making
  • Leisure activities
  • Reproductive decision maker

Appendix Table 2. Factors influencing the strength of indirect evidence for risk assessment testing

Disorder

Disease Characteristics

Impact on Defining Risk

Impact on Management

Impact on Outcomes

 

Shortened LE

Severe morbidity/disability

Moderate morbidity/disability

Minor or no morbidity/disability

Has presymptomatic stage

Determines risk in substantial proportion of patients

Known mutation in family

Penetrance is well known

There are other factors that impact clinical expression

Initiate effective interventions in presymptomatic phase

Other management changes with uncertain impact

Negative test turns off interventions

Likely to impact reproductive decision making

Definite improved health otucomes

Possible impact on outcomes, data lacking

Barriers to research

Impact on lifestyle factors

                                   
                                   

  1. Prognosis testing - Factors influencing the strength of indirect evidence

Disease Characteristics

  • Is life expectancy reduced with this disorder?
  • What is the level of physical and/or psychosocial morbidity (disability) associated with the disorder?
  • Severe morbidity/disability
  • Moderate morbidity/disability
  • Minor or no morbidity/disability

Impact of genetic test on prognosis

  • Does the genetic test have an association with prognosis of disease?
  • Does genetic testing lead to an incremental improvement in prognosis above that which can be done by usual testing?
  • Does the genetic testing allow classification of patients into clinically credible prognostic groups?
  • Have these prognostic groups been defined clinically a priori?

Impact of genetic test on management

  • Are different prognostic groups associated with different treatment interventions?
  • Type of intervention
  • Timing of intervention
  • Has treatment according to risk category been demonstrated to improve outcomes?
  • Is treatment according to risk category considered standard of care for this disorder?

Impact on Health Outcomes

  • Is there a definite improvement in health outcomes with genetic testing? For example:
  • Reclassification by prognosis leads to change in management that is known to be effective for the condition
  • Is there a possible, but not definite, improvement in health outcomes with genetic testing? For example:
  • Reclassification by prognosis leads to changes in management with uncertain impact on outcomes
  • Are there significant barriers to research, such as rarity of the disorder?
  • What is the impact of testing on lifestyle factors?
  • Employment/occupational decision making
  • Leisure activities
  • Reproductive decision maker

Appendix Table 3. Factors influencing the strength of indirect evidence – prognostic testing

Disorder

Disease Characteristics

Impact on Prognosis

Impact on Management

Impact on Outcomes

 

Shortened LE

Severe morbidity/disability

Moderate morbidity/disability

Minor or no morbidity/disability

Mutation associated with prognosis

Incremental improvement above clinical measures

Contributes to ability to make diagnosis

Clinically credible prognostic groups

Prognostic groups have different treatment

Treatment by prognostic groups improve outcomes

Treatment by prognostic group is standard of care

Definite improved health otucomes

Possible impact on outcomes, data lacking

Barriers to research

Impact on lifestyle factors

                               
                               

  1. Genetic Variants that alter response to treatment - Factors influencing the strength of indirect evidence

Disease Characteristics

  • Is life expectancy reduced with this disorder?
  • What is the level of physical and/or psychosocial morbidity (disability) associated with the disorder?
  • Severe morbidity/disability
  • Moderate morbidity/disability
  • Minor or no morbidity/disability
  • Is there effective pharmacologic therapy for this disorder?

Impact of genetic testing on assessing response to treatment

  • Can genetic testing define variants that are associated with different pharmacokinetics of drug metabolism?
  • Are these changes in drug metabolism clinically important?
  • Variants have been associated with clinically significant differences in outcomes of treatment
  • Are there genetic variants that are associated with increased risk for adverse effects?

Impact of genetic test on pharmacologic management

  • Does identification of genetic variants lead to changes in pharmacologic management?
  • Initiation of alternate agents
  • Discontinuation ineffective agents
  • Changes in dosing

Impact on Health Outcomes

  • Is there a definite improvement in health outcomes with genetic testing? For example:
  • Identification of variants leads to initiation of medications that are known to be effective
  • Is there a possible, but not definite, improvement in health outcomes with genetic testing? For example:
  • Identification of variants leads to change in pharmacologic management with uncertain impact on outcomes
  • Are there significant barriers to research, such as rarity of the disorder?

Appendix Table 3. Factors influencing the strength of an indirect evidence – genetic variants that alter response to treatment

Disorder

Disease Characteristics

Impact on response to treatment

Impact on Management

Impact on outcomes

 

Shortened LE

Severe morbidity/disability

Moderate morbidity/disability

Minor or no morbidity/disability

Effective pharmacologic therapy

Define variants with different pharmacokinetics

Different pharmacokinetics are clinically important

Variants lead to differences in outcomes

Variants with increased risk for adverse effects

Initiation of alternate agents

Discontinue ineffective treatment

Changes in dosing

Definite improved health otucomes

Possible impact on outcomes, data lacking

Barriers to research

                               
                               

History

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Date

Reason

05/13/13

New Policy. Policy created with literature search through February 2013

06/04/13

Update Related Policies. Add 12.04.86 and 4.01.21.

08/12/13

Replace policy. Additional bullet added to clarify what is meant by environmental factors (“Genetic mutations that adversely affect response to exposures in the environment that are ordinarily tolerated, such as G6PD deficiency, genetic disorders of immune function, and aminoacidopathies.”).

09/16/13

Update Related Policies; new policy 12.04.97 added.

10/17/13

Update Related Policies. Add 12.04.99, 12.04.104, 12.04.105 and 12.04.106.

11/20/13

Update Related Policies. Add 12.04.102.

12/19/13

Update Related Policies. Change title to 12.04.75.

01/03/14

Update Related Policies; add new policies 12.04.103, 12.04.107, 12.04.108, 12.04.109, 12.04.110 and 12.04.111, all effective 12/9/13.

01/16/14

Update Related Policies. Change title to 12.04.504.

02/27/14

Update Related Policies. Change title to 12.04.48, add 12.04.113, and 12.04.114.

05/23/14

Update Related Policies. Add 2.04.115, 2.04.118, 2.04.119 and 12.04.509. Remove 12.04.82 as it was deleted.

07/14/14

Annual Review. Policy statements unchanged. No new literature has been identified for this concept policy update. Expanded framework for determining clinical utility has been added as an appendix for the four categories of diagnostic testing, risk assessment, prognostic testing, and pharmacogenomics.

12/01/14

Update Related Policies. Add 12.04.121.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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