BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Tests (Miscellaneous)
Chapter: Genetic Testing
Current Effective Date: February 01, 2014
Original Effective Date: September 01, 2007
Publish Date: January 14, 2014
Revised Dates: September 13, 2013; January 14, 2014

Learning the secrets of the human gene is revolutionizing our understanding of the genetic basis of disease. Certain genetic mutations may predispose susceptible individuals to the development of specific diseases. Therefore, genetic testing has dramatically expanded the ability to predict, diagnose, and treat these diseases. Many of the tests are moving quickly from the research setting to the marketplace without the benefit of U. S. Food and Drug Administration (FDA) review. These tests have the potential to reshape disease prevention and treatment by identifying inherited mutations and/or susceptibility to cancer.

The National Institutes of Health (NIH) describes the available types of genetic testing as:

  • Newborn screening:  Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. The routine testing for certain metabolic disorders is the most widespread use of genetic testing.
  • Diagnostic testing:  Diagnostic testing is used to diagnose or rule out a specific genetic chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed at any time during a person’s life, but is not available for all gene or all genetic disorders. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.
  • Carrier testing:  Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing may be offered to individuals who have a family history of a genetic disorder and to people in ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide statistical information about the likelihood of a couple’s risk of having a child with a particular genetic condition.
  • Late-onset disorder testing:  Late-onset disorder testing is frequently done for diseases, such as cancer or heart disease that generally occur in adulthood. These diseases may be complex and have both genetic and environmental causes. This type of testing may indicate a susceptibility or predisposition for these diseases. This testing may be considered either diagnostic or predictive and presymptomatic testing (further explained below).
  • Prenatal testing:  Prenatal testing is used to detect abnormalities or changes in a fetus’s genes or chromosomes before birth. This type of testing may be offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder. In some cases, prenatal testing can provide statistical information about a potential for an abnormality, which can help the couple prepare, including consideration of whether to abort the pregnancy. It cannot identify all possible inherited disorders or birth defects.
  • Preimplantation testing:  Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that uses genetic testing to identify the chromosomal structure of an embryo, and so potentially identify an embryo with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques (ART), such as in-vitro fertilization (IVF). IVF involves removing egg cells from a woman’s ovaries and fertilizing the sperm cells outside the body. To perform PGD, a small number of cells are taken from the embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.
  • Predictive and presymptomatic testing:  Predictive and presymptomatic tests are utilized to identify gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no sign 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. Presymptomatic testing can provide statistical information about the potential of an individual to develop a genetic disorder, before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide statistical information about a person’s risk of developing a specific disorder and help the individual or family with making decisions about future medical care.
  • Forensic testing:  Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the types of tests described earlier, forensic testing is not used to detect gene mutations associated with diseases. It may be considered identification testing.
  • Research testing:  Research testing includes finding unknown genes, learning how genes work and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers.

Generally, most genetic testing is voluntary. Because genetic testing has benefits and limitations, the decision whether to be tested is personal and complex for the patient. Counseling and informed consent are part of the decision process before proceeding with the genetic tests.

Traditionally, genetic tests have been available only through a healthcare provider who orders the appropriate test from a laboratory, collects and sends the testing samples, and interprets the results. Recently, direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television media sales, print advertisements, or the Internet. This form of testing provides access to a patient’s genetic information without necessarily involving a healthcare provider, counselor or healthcare carrier. Once purchased by the consumer, the at-home genetic tests are mailed to the consumer who collects a sample of cells by swabbing the inside of the check and sending the sample by return mail back to the particular laboratory or vendor. In some cases, the at-home genetic test company requires the patient to visit a health clinic to have blood drawn, sending the sample back to the laboratory. Patients may be notified of their results by mail, telephone, or e-mail, or the results are posted online. In some cases a genetic counselor or healthcare provider service is available to explain results and answer questions, sometimes at additional costs. 

Genetic tests are performed on samples of blood, hair, skin, amniotic fluid, or other bodily tissue. The sample is sent to a specialized laboratory where technicians look for specific changes in chromosomes, deoxyribonucleic acid (DNA), enzymes, or proteins depending on the suspected disorder. 

The cost of genetic testing can range from under $100 to more than $2,000 per test, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members are tested to obtain meaningful results, for example, to determine if follow-up care or monitoring are necessary. 

From the date that a sample is obtained, the test results may be available in several weeks to months. The healthcare provider ordering the genetic tests can provide more specifics about the cost and time frame associated with the genetic test(s) ordered.

PMP22 (e.g., Charcot-Marie-Tooth [CMT])

Charcot-Marie-Tooth (CMT) is a common inherited neurological disorder, also known as hereditary motor and sensory neuropathy or peroneal muscle atrophy, is a neuropathy that affects both motor and sensory nerves. There are many forms of CMT disease, including CMT1, CMT2, CMT3, CMT4, and CMTX. CMT1, caused by abnormalities in the myelin sheath, has three main types. CMT1A is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). The PMP-22 protein is a critical component of the myelin sheath. Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. Patients experience weakness and atrophy of the muscles of the lower legs beginning in adolescence; later they experience hand weakness and sensory loss. Interestingly, a different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy. (22)

FBN1 mutation TGFBR1, TGFBR2 (e.g., Marfan Syndrome)

Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 mutations associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil, seen in approximately 60% of affected individuals, is a hallmark feature. People with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation. The skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia). Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is common and can be mild or severe and progressive. The major sources of morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population. (27)

In 1995, a group of the world’s leading clinicians in Marfan syndrome proposed the Ghent diagnostic criteria, which identified major and minor findings, based on clinical observation of various organ systems and on family history. In 2010 the Ghent diagnostic criteria were revised, putting more weight on the cardiovascular manifestations, making aortic root aneurysm and ectopia lentis the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of Marfan syndrome. In the absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. In the revised Ghent diagnostic criteria, FBN1 testing has greater weight in the diagnostic assessment. (28)

In addition, the revised Ghent criteria state that special consideration should be given to young individuals (<20 years old) because in sporadic cases these individuals may not fit into one of the four proposed scenarios. If they have insufficient systemic features (<7) and/or borderline aortic disease (Z<3), without FBN1 mutation, Ghent suggests using the term “non-specific connective tissue disorder” until follow-up echocardiogram shows aortic root dilation (Z≥3). If an FBN1 mutation is identified but aortic root is below Z=3, use the term “potential Marfan syndrome” until the aorta reaches threshold. In adults (>20 years old) Ghent defines three main categories of alternative diagnoses: ELS (ectopia lentis syndrome); MASS phenotype (myopia, mitral valve prolapse, borderline aortic root enlargement [Z<2], skin and skeletal findings); and MVPS (mitral valve prolapse syndrome). (34)


  • In absence of family history:
  1. Presence of aortic root dilation (Z-score ≥2 when standardized to age and body size) or dissection, AND ectopia lentis = Marfan syndrome*; or
  2. Presence of aortic root dilation (Z-score ≥2) or dissection, AND identification of FBN1 mutation = Marfan syndrome; or
  3. Aortic root dilation (Z-score ≥2) or dissection is present, but ectopia lentis is absent, AND FBN1 status is either unknown or negative, AND systemic features score is ≥7*; or
  4. Presence of ectopia lentis, but no known aortic disease, AND presence of FBN1 with known association to aortic disease = Marfan syndrome.
  • In the presence of family history, i.e., a family member has been diagnosed with Marfan syndrome, using above criteria:
  1. Presence of ectopia lentis, or
  2. Systemic features score ≥7 points*; or
  3. Presence of aortic root dilatation, with Z-score ≥2 in adults (≥20 years old) or Z-score ≥3 in individuals <20 years old*

*Caveat:  Features of SGS, LDS or vEDS (as defined in Table 1) must be excluded AND appropriate alternative genetic testing (TGFBR1/2, collagen biochemistry, COL3A1, and other indicated genetic testing if indicated) should be performed.


  • Ectopia lentis with or without systemic features score AND with an FBN1 not known to be associated with aortic disease or no FBN1 = ectopia lentis syndrome (ELS)
  • Aortic disease (Z <2) AND systemic features (score ≥5 with at least one skeletal feature) without ectopia lentis = MASS (myopia, mitral valve prolapse, borderline aortic disease (Z <2), striae, skeletal findings phenotype)
  • Mitral valve prolapse AND aortic disease (Z <2) AND systemic features score <5 = mitral valve prolapse syndrome (MVPS)




Wrist AND thumb sign


Wrist OR thumb sign


Pectus carinatum deformity


Pectus excavatum or chest asymmetry


Hindfoot deformity


Plain pes planus (flat feet)




Dural ecstasia


Protrusio Acetabuli


Reduced upper segment to lower segment ratio AND increased arm/height AND no severe scoliosis


Scoliosis or thoracolumbar kyphosis


Reduced elbow extension


Facial features (3 of 5: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasis, retrognathis)


Skin striae


Myopia > 3 diopters


Mitral valve prolapse (all types)


Maximum score = 20 points; score ≥ 7 points indicates systemic involvement

TABLE 1 Features of Differential Diagnosis

Differential Diagnosis


Discriminating Features

Loeys-Dietz syndrome (LDS)


Bifid uvula/cleft palate, arterial tortuosity, hypertelorism, diffuse aortic and arterial aneurysms, craniosynostosis, clubfoot, cervical spine instability, thin and velvety skin, easy bruising

Shprintzen-Goldberg syndrome (SGS)

FBN1 and other

Craniosynostosis, mental retardation/intellectual disability

Congential contracture arachnodactyly (CCA)


Crumpled ears, contractures

Weill-Marchesani syndrome (WMS)


Microspherophakia, brachydactyly, joint stiffness

Ectopia lentis syndrome (ELS)




Lack of aortic root dilatation



Thrombosis, mental retardation/intellectual disability

Familial thoracic aortic aneurysm syndrome (FTAA)

FTAA with bicuspid aortic valve (BAV)



Lack of Marfanoid skeletal features, levido reticularis, iris flocculi

FTAA with patent ductus arteriosus (PDA)



Arterial tortuosity syndrome (ATS)


Generalized arterial tortuosity, arterial stenosis, facial dysmorphism

Ehlers-Danlos syndromes (vascular, valvular, kyphoscoliotic type)




Middle sized artery aneurysm, severe valvular insufficiency, translucent skin, dystrophic scars, facial characteristics


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


A.  PMP22 Mutation Analysis (e.g., Charcot-Marie-Tooth)

PMP22 (e.g., Charcot-Marie-Tooth [CMT]) may be considered medically necessary for the following:

  1. To confirm a diagnosis in an individual with suspected Charcot-Marie-Tooth (CMT) disease based on clinical findings; or
  2. Predictive testing in asymptomatic individual with a family history of CMT1A; or
  3. To avoid adverse effects of Vincristine treatment in oncology patients with unexplained or preexisting familial neuropathy.

Genetic testing for PMP22 mutation analysis is considered experimental, investigational and unproven for any other indications.

B.  FBN1, TGFBR1, or TGFBR2 Mutation Analysis (e.g., Marfan syndrome)

FBN1 mutation TGFBR1, TGFBR2 (e.g., Marfan syndrome) may be considered medically necessary for the following:

  1. To facilitate the diagnosis of Marfan syndrome in individuals who do not fulfill the Ghent diagnostic criteria*, but have at least 1 major feature of the condition; or
  2. Asymptomatic at-risk individual with a known disease-causing mutation in the family.

*NOTE: See Ghent Diagnostic Criteria Table in Description section

Genetic testing for FBN1, TGFBR1, and TGFBR2 mutation analysis is considered experimental, investigational and unproven for any other indications.

C.  Other Miscellaneous Genetic Tests (e.g., Home tests, other miscellaneous genetic tests)

Direct-to-consumer genetic testing (e.g., gene health testing, at-home genetic testing, etc.) with self-administered or self-directed at-home testing kits, with or without physician written prescription or verbal recommendation, is considered not medically necessary. NOTE: Genetic testing kits are sold by telephone, e-mail, Internet, or other media. The kits are mailed directly to consumers. The consumer obtains samples, such as cells at home or blood at a local health clinic, then sends the samples to a particular laboratory or manufacturer for processing.

D. Miscellaneous

At-Home genetic counseling (pre- or post-test) associated with self-administered or self-directed at-home testing kits, with or without physician written prescription or verbal recommendation, is considered not medically necessary.

Miscellaneous—A variety of Medical Policies continue to be developed to address genetic testing for specific conditions, risk or susceptibility. This policy applies only if there is not a separate Medical Policy that outlines specific criteria for testing. Genetic testing for any condition that is not addressed in a specific Medical Policy is considered experimental, investigational and/or unproven. If a separate policy does exist, then the criteria for medical necessity in that policy supersede the guidelines in this policy.

NOTE:  Genetics counselling is strongly recommended prior to performing genetic testing.

NOTE:  For policy descriptions and coverage information for specific genetic tests (such as genetic testing for susceptibility of cancer or other conditions), please refer to the specific Medical Policy.

NOTE: For preimplantation genetic testing (PGT) please see Medical Policy Preimplantation Genetic Testing (PGT).

NOTE: For prenatal and preconception genetic testing and fetal aneuploidy, please see Medical Policy Prenatal and Preconception Genetic Tests.


Genetic testing analyzes chromosomes, genes or gene products to detect mutations that may be predictive of certain inheritable diseases, such as cancer, sickle cell anemia, and Down syndrome. Currently, inherited gene mutations are thought to contribute to more than 4,000 diseases or disorders. Other genetic and environmental factors, lifestyle choices, and family medical history also affect a patient’s risk of developing many diseases or disorders. The determination of whether the genetic factor(s) or environmental factor(s) predominate in an individual’s situation is often unclear. These factors are discussed during a consultation with a professional genetic counselor, medical geneticist, or healthcare provider, but not addressed by at-home genetic tests. Genetic testing provides only one piece of information about a patient’s health.

The growing market for DTC, at-home, genetic testing purport to promote awareness of genetic diseases, allow patients to take a more proactive role in their health care, and offer a means for patients to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Patients are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health and future healthcare. Patients may also experience an invasion of genetic privacy if testing companies use genetic information in an unauthorized way. More research and oversight is required to fully understand the benefits and limitations of DTC, at-home, genetic testing.

Genetic tests are developed in two ways: manufacturers who package and sell genetic tests as kits or multiple laboratories that develop genetic tests under the FDA guidance and clearance process. The later requires FDA pre-market review that involves an analysis of the test’s accuracy, precision or repeatability, and analytical validity. However, most new genetic tests are developed by individual laboratories for their own use and may be marketed as DTC utilization. While the FDA at this time does not regulate at-home laboratory tests, it does require certain controls, such as good manufacturing practices.

With over 1,000 genetic tests currently available for healthcare providers to manage patient care and/or treatment, the practice of genetic medicine is shifting from research-academic based utilization to the primary care provider’s office, or mail-order. It is the responsibility of the healthcare provider, the primary care clinician, genetic counselor or medical geneticist, to correctly use and interpret the genetic tests, by knowing the correct test to order to elicit the information desired, by knowing the limitations of that specific test, and by knowing how to determine the medical management for the patient and/or family from the test results. As the availability and utilization of genetic tests expand, this becomes increasingly difficult for the healthcare provider, perhaps being ill prepared to use the genetic tests effectively, particularly those that have been self-ordered. Genetic tests have moved rapidly into the market place without benefit of randomized controlled trials to establish efficacy.

Gene testing may have potential benefits. A negative result, such as no change in the gene, chromosome, or protein under consideration, can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result, such the determination of a change in the sequence in the gene, chromosome, or protein under consideration, can direct a patient toward available prevention, monitoring, and treatment options. However, genetic tests generally provide a statistical probability only of a clinical abnormality; environmental factors and/or other genetic factors may result in equally or more significant factors in the development of any abnormality with clinical significance. Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a patient will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. The genetics professional, in some cases, is prepared to explain in detail the benefits, risks, and limitations of a particular test. It is important that a patient who is considering genetic testing understand and weigh these factors, before making a decision.

Genetic tests function in two environments: the laboratory and the clinic. Genetic tests are evaluated based primarily on three characteristics: analytical validity, clinical validity, and clinical utility.

  1. Analytic validity is defined as the ability of a test to detect or measure analyte (a substance or chemical constituent undergoing analysis) it is intended to detect or measure. This characteristic is critical for all clinical laboratory testing, not only genetic testing, as it provides information about the ability of the test to perform reliably at its most basic level.
  2. Clinical validity of a genetic test is its ability to accurately diagnose or predict the risk of a particular clinical outcome. A genetic test’s clinical validity relies on an established connection between the DNA variant being tested to a specific health condition. Many measures are used to assess clinical validity, but the two of key importance are clinical sensitivity and positive predictive value (PPV). Most genetic tests can be either diagnostic or predictive and, therefore, the measures used to assess the clinical validity of a genetic test must take this into consideration. For the purposes of a genetic test, PPV is the test measure most commonly used by providers to gauge the usefulness of a test to clinical management of patients. Determining the PPV of a predictive genetic test may be difficult because there are many different DNA variants and environmental modifiers that may affect the development of a disease. Clinical sensitivity may be defined as the probability that people who have, or will develop a disease, are detected by the test.
  3. Clinical utility takes into account the impact and usefulness of the test results to the patient and the family, and primarily considers the implications that the test results have for health outcomes and whether the outcome of the test affects the patient’s health outcome in a positive way (for example, is the treatment or preventive care available for the disease). It also includes the utility of the test more broadly for society, and can encompass considerations of the psychological, social and economic consequences of testing.

As genetic research advances, more tests will become available, enhanced marketing to providers and the public, greater test sensitivity, advancing test outcome predictability, and diagnosing or predicting diseases before the ability to prevent or treat the disease.

HCSC Medical Policies have been, and continue to be, developed to focus on specific diseases or conditions. Genetic tests that are not addressed on a specific Medical Policy remain experimental, investigational and unproven due lack of evidence in the peer-reviewed medical literature that:

  • permits conclusions on the effect of the genetic test on health outcomes.
  • demonstrates an improvement in net health outcome through use of  the genetic test.

2011 Update

United States Government Accountability Office (GAO) published a report on their investigation of four direct-to-consumer genetic tests, 23andMe, deCode Genetics, Navigenics, and Pathway Genomics. Their report included the following.

“Scientists increasingly believe that most, if not all, diseases have a genetic component. Consequently, genetic testing is becoming an integral part of health care with great potential for future test development and use. Some genetic tests are sold directly to the consumer via the Internet or retail stores, and purport to use genetic information to deliver personalized nutrition and lifestyle guidance. These tests require consumers to self-collect a sample of genetic material, usually from a cheek swab, and then forward the sample to a laboratory for analysis. Companies that market this type of test claim to provide consumers with the information needed to tailor their diet and exercise programs to address their genetically determined health risks.

GAO was asked to investigate the ‘legitimacy’ of these claims. This testimony reflects the findings of GAO’s investigation of a nonrepresentative selection of genetic tests. Specifically, GAO purchased tests from four Web sites and created ‘fictitious consumers’ by submitting for analysis 12 DNA samples from a female and two samples from an unrelated male, and describing this DNA as coming from adults of various ages, weights, and lifestyle descriptions. GAO also consulted with experts in genetics and nutrition. The results from all the tests GAO purchased mislead consumers by making predictions that are medically unproven and so ambiguous that they do not provide meaningful information to consumers. Although there are numerous disclaimers indicating that the tests are not intended to diagnose disease, all 14 results predict that the fictitious consumers are at risk for developing a range of conditions. However, although some types of diseases, such as cystic fibrosis, can be definitively diagnosed by looking at certain genes, the experts GAO spoke with said that the medical predictions in the tests results can not be medically proven at this time. Even if the predictions could be medically proven, the way the results are presented renders them meaningless. For example, many people ‘may’ be ‘at increased risk’ for developing heart disease, so such an ambiguous statement could relate to any human that submitted DNA. Results from the tests that GAO purchased from Web sites 1 and 4 further mislead the consumer by recommending costly dietary supplements. The results from the tests from Web site 1 suggested ‘personalized’ supplements costing approximately $1, 200 per year. However, after examining the list of ingredients, GAO found that they were substantially the same as typical vitamins and antioxidants that can be found in any grocery store for about $35 per year. Results from the tests from Web site 4 suggested expensive products that claimed to repair damaged DNA. However, the experts GAO spoke with stated that there is no ‘pill’ currently available that has been proven to do so. The experts also told us that, in some circumstances, taking supplements such as those recommended may be harmful.

In addition, results from the tests that GAO purchased from Web sites 1, 2, and 3 do not provide recommendations based on a unique genetic profile as promised, but instead provide a number of common sense health recommendations. If the recommendations were truly based on genetic analysis, then the nine fictitious consumers that GAO created for these sites using the female DNA should have received the same recommendations because their DNA came from the same source. Instead, they received a variety of different recommendations, depending on their fictitious lifestyles. For example, when GAO created lifestyle descriptions stating that the consumers smoked, they received recommendations to stop smoking. In contrast, if GAO said the consumers never smoked, they received recommendations to continue to avoid smoking.

The current regulatory environment provides only limited oversight to those developing and marketing new types of genetic tests. Consequently, companies that sell nutrigenetic tests like the ones we purchased may mislead consumers by promising results they cannot deliver. Further, the unproven medical predictions these companies can include in their test results may needlessly alarm consumers into thinking that they have an illness or that they need to buy a costly supplement in order to prevent an illness. Perhaps even more troubling, the test results may falsely assure consumers that they are healthy when this may not be the case.”

A search of peer reviewed literature through July 2011 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.

2012 Update

PMP22 Mutation Analysis (e.g., Charcot-Marie-Tooth)

Charcot Marie Tooth disease (CMT) affects one in 2500 people and is caused by mutations in more than 30 genes. (22) Saporta et al. analyzed data from 1024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. They identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Of 1024 patients evaluated, 787 received CMT diagnoses. Five hundred twenty-seven patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, HNPP, CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had more than one genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Combining features of the phenotypic and physiology groups allowed identification of patients who were highly likely to have specific subtypes of CMT. (24)

In 2009, the American Academy of Neurology, the American Association of Neuromuscular and

Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation published a Practice Parameter based on an evidence-based review of the role of laboratory and genetic testing to evaluate distal symmetric polyneuropathy. (26) A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. Recommendations included:

  • Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies.
  • Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening.
  • There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype.

A September, 2012 TEC Specialty Pharmacy Report on Vincristine Liposome Injection clinical Applications and Conclusions, prepared by Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC), stated a demyelinating condition such as Charcot-Marie-Tooth as an exclusion due to neurotoxic effects of Vincristine. (24)

FBN1, TGFBR1, or TGFBR2 Mutation Analysis (e.g., Marfan syndrome)

Due to the wide range of symptoms of Marfan syndrome, definitive diagnosis is complex, and requires sequencing of a large gene, FBN1. (29)

Sakai et al. did a comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome. (30)

Miscellaneous Genetic Testing

A search of peer reviewed literature through October 2012 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.


Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

190.5, 277.00, 282.43, 282.47, 282.5, 289.81, 330.0, 332.0, 333.4, 335.20, 340, 389.8, 710.1, 710.1, 710.1, 710.1, 758.0, 759.6, 796.5, 796.5, V18.9, V77.6, V78.2, V82.71, V82.79, V83.01, V83.02, V83.81, V83.89, V84.01, V84.02, V84.03, V84.04, V84.09, V84.81, V84.89

ICD-10 Codes

C69.20, E75.21, E75.22, E75.240, E75.241, E75.242, E75.243, E75.248, E75.249, E84.9, D56.0, D56.5, D57.3, D68.51, E75.29, G20, G10, G12.21, G35, H91.8X9, M34.0, M34.1, M34.9, Q85.8, Z84.81, Z13.79, Z14.01, Z14.02, Z14.1, Z14.8, Z15.01, Z15.02, Z15.03, Z15.04, Z15.09, Z15.81, Z15.89

Procedural Codes: 81205, 81245, 81250, 81261, 81262, 81263, 81264, 81287, 81302, 81303, 81304, 81310, 81315, 81316, 81324, 81325, 81326, 81331, 81340, 81341, 81342, 81350, 81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479, 81599, 96040, S3800, S3841, S3842, S3844, S3853, S5190
  1. Medical Management Policy Statements on Genetic Testing. Chicago, Illinois: Blue Cross Blue Shield Association National Council on Medical Management (1997 June 27) White Paper.
  2. Human Genome – Holtzman, N.A., and M.S. Watson. Promoting Safe and Effective Genetic Testing in the United States (1997 September). National Institutes of Health Task Force – Department of Energy Working Group on Ethical, Legal, and Social Implications of Human Genome Research. (accessed – 2007 March 3). Available at .
  3. HHS – A Public Consultation on Oversight of Genetic Tests (1999 December 1 through 2000 January 31). National Institutes of Health and Health and Human Services – Secretary’s Advisory Committee on Genetic Testing. (accessed – 2007 March 5). Available at .
  4. HHS – Ensuring the Safe and Appropriate Use of Genetic Tests  (2001 January 29). Health and Human Services – Secretary’s Advisory Committee on Genetic Testing. (accessed 2007 March 2). Available at .
  5. Gollust, S.E., Hull, S.C., et al. Limitations of direct-to-consumer advertising for clinical genetic testing. Genetic Medicine (2002 October 9) 288(14): 1762-7.
  6. Burke, W. Genetic Testing. The New England Journal of Medicine (2002 December 5) 23(347): 1867-75.
  7. JCO – American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility (2003 March 1). American Society of Clinical Oncology (ASCO) Special Article printed in Journal of Clinical Oncology (2003 June) 21(12): 2397-2406. (accessed – 2007 May 31). Available at .
  8. Gollust, S.E., Wilfond, B.S., et al. Direct-to-consumer sales of genetic services on the Internet. Genetic Medicine (2003 July – August) 5(4): 332-7.
  9. Wasson, K., Cook, E.D., et al. Direct-to-consumer online genetic testing and the four principles: An analysis of the ethical issues. Ethics Medicine (2006 Summer) 22(2): 83-91.
  10. Grosse, S.D., and M.J. Khoury. What is the clinical utility of genetic testing? Genetics in Medicine (2006 July) 8(7): 448-50.
  11. Kurtz, G. Nutrigenetic Testing—Tests Purchased from Four Web Sites Mislead Consumers. United States Government Accountability Office Testimony Before the Special Committee on Aging, U.S. Senate. GAO-06-977T  (2006, July) Available at (accessed 2011 July).
  12. CDC – Evaluation of Genetic Testing (2007 January 11). ACCE: A CDC-Sponsored Project Carried Out by the Foundation of Blood Research, National Office of Public Health Genomics. (accessed – 2007 March 2). Available at .
  13. Sarata, A.K. CRS Report for Congress – Genetic Testing: Scientific Background for Policy Makers, Congressional Research Service (2007 January 26): 1-9.
  14. NIH – Handbook – Genetic Testing, Your Guide to Understanding Genetic Testing (2007 February 16). National Institutes of Health and National Library of Medicine – Lister Hill National Center for Biomedical Communications, University of Washington. (accessed – 2007 February 21). Available at <>.
  15. DNA – Genetic Testing Practice Guidelines: Translating Genetic Discoveries into Clinical Care (2007 March 6). Genetics and Public Policy Center. (accessed – 2007 March 8). Available at .
  16. AMP – Leonard, D.G.B., Voelkerding, K.V., et al. Genetics, AMP Response to the DHHS Secretary’s Advisory Committee on Genetic Testing (2007 May 27). Association of Molecular Pathology. (accessed – 2007 May 31). Available at .
  17. Daly MB, Axilbund JE, et al. Genetic/familial high-risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology Version 1.2012.
  18. Charcot-Marie-Tooth disease fact sheet. NIH Publication No 07-4897. Prepared by the Office of Communications and Public Liason, National Institute of Neurological Disorders and Stroke. Last updated February 15, 2011.
  19. Kedlaya D, Calhoun JH, et al. Charcot-Marie-Tooth disease workup. Medscape September 24, 2012. Available at (accessed October 26, 2010).
  20. Vincristine liposome injection (Mariqibo®). TEC Specialty Pharmacy Report #10-2012 Blue Cross Blue Shield Association. Chicago, Illinois. September 2012.
  21. Saporta ASD, Sottile BA, et al. Charcot-Marie-Tooth (CMT) Subtypes and Genetic Testing Strategies. Ann Neurol January 2011; 69:22-23, doi:10.1002/ana.22166.
  22. England JD, Gronseth GS, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review): report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009; 184-192.
  23. Dietz HC, et al. Marfan Syndrome. Institute of Genetic Medicine. Johns Hopkins University School of Medicine. Baltimore, MD. December 1, 2011. Available at (accessed October 30, 2012).
  24. Loeys BL, Dietz HC, et al. The revised Ghent criteria for the Marfan syndrome. J Med Genet 2010; 47:476-485.
  25. Sheikhzadeh S, Kusch ML, et al. A simple clinical model to estimate the probability of Marfan syndrome. QJM. 2012 June; 105(6):527-35. Epub 2012 Feb 1.
  26. Sakai H, Visser R, Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J Med Genet A. 2006 Aug 15; 140(16):1719-25.
  27. Nonsyndromic deafness—Genetics Home reference. US National Library of Medicine November, 2006.
  28. Smith RJH, Van Camp G, et al. Non syndromic hearing loss and deafness, DFNB1. National Library of Medicine, National Institutes of Health. July 14, 2011.
  29. Smith RJH, Van Camp G, et al. Non syndromic hearing loss and deafness, DFNA3. National Library of Medicine, National Institutes of Health. April 19, 2012.
  30. Loeys BL, Dietz HC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47:476-485.
November 2011 Policy reviewed: updated medical necessity statement and removed "all of the following" and added "...the member has one or more of the following."
January 2012 Removed Familial Cutaneous Malignant Melanoma from investigational statement.
September 2013 Policy formatting and language revised.  Title changed from "Genetic Testing" to "Genetic Tests (Miscellaneous)".
February 2014 Document updated. The following was removed from Coverage: Genetic testing for GJB2and GJB6 (e.g., non-syndromic hearing loss) is considered experimental, investigational and unproven. This topic is now addressed on new Medical Policy Genetic Testing for Nonsyndromic Hearing Loss. The following was added to Coverage: Genetics counselling is strongly recommended prior to performing genetic testing. CPT/HCPCS code(s) updated.  
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Genetic Tests (Miscellaneous)