General Approach to Genetic Testing

Number 12.04.91

Effective Date August 12, 2013

Revision Date(s) 08/12/13

Replaces N/A


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


Sequencing-based Tests to Determine Trisomy 21 from Maternal Plasma DNA


Genetic Testing for Familial Alzheimer's Disease


Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy


Gene-Based Tests for Screening, Detection, and/or Management of Prostate Cancer


Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis In Patients With Breast Cancer


Cytochrome p450 Genotyping


Genetic Testing for Cardiac Ion Channelopathies


Genetic Testing for Cutaneous Malignant Melanoma


Genetic Testing for Warfarin Dose


Genetic Testing for Tamoxifen Treatment


PathFinder TG® Molecular Testing


Microarray-based Gene Expression Testing for Cancers of Unknown Primary Origin


Non-BRCA Breast Cancer Risk Assessment


Chromosomal Microarray (CMA) Analysis for the Genetic Evaluation of Patients with Developmental Delay/Intellectual Disability or Autism Spectrum Disorder


JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms


Multigene Expression Assay for Predicting Recurrence in Colon Cancer


Use of Common Genetic Variants to Predict Risk of Non-Familial Breast CancerAssessment


Systems Pathology for Predicting Risk of Recurrence in Prostate Cancer


Serum Biomarker Human Epididymis Protein 4 (HE4)


KIF6 Genotyping for Predicting Cardiovascular Risk and/or Effectiveness of Statin Therapy


Genetic Testing for Lipoprotein(a) Variant(s) as a Decision Aid for Aspirin Treatment


Genotyping for 9p21 Single Nucleotide Polymorphisms to Predict Risk of Cardiovascular Disease or Aneurysm


Gene Expression Testing to Predict Coronary Artery Disease


DNA-Based Testing for Adolescent Idiopathic Scoliosis


Genetic Testing of CADASIL Syndrome


BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF Inhibitor Targeted Therapy


Mutation Analysis in Fine Needle Aspirates of the Thyroid


Genetic Testing for Hereditary Hemochromatosis


Genetic Testing for Rett Syndrome


Genetic Testing for Inherited Thrombophilia


Genetic Testing for FMR1 mutations (including Fragile X Syndrome)


Genetic Testing for Duchenne and Becker Muscular


Genetic Testing for PTEN Hamartoma Tumor Syndrome


Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies including Charcot-Marie-Tooth


General Approach to Evaluating the Utility of Genetic Panels


Genetic Testing for Lactase Insufficiency


Human Leukocyte Antigen (HLA) Testing for Celiac Disease


Genetic Testing for Statin Induced Myopathy


Microarray-Based Gene Expression Profile Testing for Multiple Myeloma Risk Stratification


Genetic Testing for Hereditary Pancreatitis


Whole Exome Sequencing


Genetic Testing for Macular Degeneration


Genetic Testing for Alpha Thalassemia


Genetic Testing for Facioscapulohumeral Muscular Dystrophy (FSHMD)


Genetic Testing for CHARGE Syndrome


Carrier Testing for Genetic Diseases


Fetal RHD Genotyping Using Maternal Plasma


Genetic Testing for Epilepsy


Genecept Assay


Microarray-based Gene Expression Profile Analysis for Prostate Cancer Management


Analysis of MGMT Promoter Methylation in Malignant Gliomas


Genetic Testing for Dilated Cardiomyopathy


Preimplantation Genetic Testing in Embryos


Genetic Testing for Hereditary Breast and/or Ovarian Cancer


Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Policy Guidelines



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 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 non-medical 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.

This policy does not include cytogenetic testing (karyotyping to analyze the total number and structure of the chromosomes), biochemical testing or molecular testing for infectious disease.

This policy does not address prenatal testing.

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 their 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.


There are numerous commercially available genetic tests, including those used to guide intervention in symptomatic or asymptomatic individuals, to identify individuals 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.



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.


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 individual 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 individuals (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: The study of how an individual’s genetic makeup affects the body’s response to drugs.


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.

Benefit Application



General principles for evaluating genetic tests

The test should be cleared or approved by the FDA, or performed in a CLIA-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) the analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; 2) the clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and 3) the clinical utility of the test, i.e., how the 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 individual. This refers to a molecular diagnosis defined by the presence of a known pathologic mutation. For the purposes of genetic testing, a symptomatic individual is defined as an individual 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 individuals 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 an individual’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 an individual has a genetic mutation that may lead to development of the disease.
  2. Carrier testing is performed in an individual who may be at risk of passing on a mutation to their children. This type of testing is offered to individuals 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

a. 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.

b. 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)

c. 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 such as phenylketonuria (PKU).

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 individual

a. An association of the marker with the disorder has been established AND

b. Symptoms of the disease are present AND

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

d. The clinical utility of a diagnosis has been establish, in 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

e. Establishing the diagnosis by genetic testing will end the clinical work-up for other disorders.

  1. Risk assessment

a. Predictive and presymptomatic:

  • An association of the marker with future disorder has been established AND
  • Testing will lead to improved health outcomes based on prevention or early detection strategies

b. 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 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. The clinical utility of identifying the mutation has been established, in that it will lead to changes in clinical management of the condition or changes in surveillance.
  1. Genetic variants that later response to treatment or to an environmental factor
  1. Constitutional (germline) testing:
  • The association of the marker with a phenotype/metabolic state that relates to drug efficacy or adverse drug reactions has been established AND
  • 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 upon drug selection or dosage.
  1. Tissue specific tumor testing:
  • The association of a mutation with response to a particular drug has been establish AND
  • The association of a mutation with response to a particular drug has been established AND

The patient is a candidate for targeted drug therapy which is associated with a specific mutation.


  1. Last accessed May 22, 2013.
  2. Last accessed May 22, 2013.
  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.







Molecular diagnostics, code range



Molecular pathology procedure code range



Unlisted molecular pathology procedure







New Policy. Policy created with literature search through February 2013


Update Related Policies. Add 12.04.86 and 4.01.21.


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.”).


Update Related Policies; new policy 12.04.97 added.


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


Update Related Policies. Add 12.04.102.


Update Related Policies. Change title to 12.04.75.


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.


Update Related Policies. Change title to 12.04.504.


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

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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