Coverage Policy Manual
Policy #: 2015013
Category: Laboratory
Initiated: May 2015
Last Review: May 2023
  Genetic Test: Fanconi Anemia

FA is an inherited disorder that is characterized by congenital abnormalities, bone marrow failure, and predisposition to hematologic malignancies. It is a rare disorder with an incidence of less than 10 per million live births (Sakaguchi, 2013).  FA is usually transmitted by the autosomal recessive route and by the X-linked route in a very small number of cases. The carrier frequency in the United States is approximately 1 in 300 for the general population, and as high as 1 in 100 for certain populations such as Ashkenazi Jews.
The clinical expression of FA is variable, but it is associated with early mortality and a high degree of morbidity. Approximately 60% to 70% have at least 1 congenital abnormality, most common being disorders of the thumb and radial bones, short stature, skin hyperpigmentation, hypogonadism, and café au-lait spots (Khincha, 2013). A variety of other abnormalities of internal organs such as the heart, lungs, kidneys, and gastrointestinal tract can occur in up to 20% to 25% of patients (Shimamura, 2010).  The most serious clinical problems are bone marrow abnormalities and malignancies. Hematologic abnormalities and bone marrow failure generally present in the first decade of life, although they can present much later (Zhang, 2014). There is an increased predisposition to malignancies, especially myelodysplastic syndrome, acute myeloid leukemia, and squamous cell cancers of the head and neck (Kutler, 2003).
For patients with suspected FA after clinical and hematologic examination, the diagnosis can be confirmed by chromosome breakage analysis. A positive chromosome breakage test after exposure to alkylating agents such as diepoxybutane or mitomycin C confirms the diagnosis of FA, and a negative test rules out FA. However, results may sometimes be inconclusive, leaving uncertainty as to the diagnosis of FA.8 In these cases, the detection of a genetic mutation that is known to be pathogenic for FA can confirm the diagnosis.
Other inherited bone marrow failure disorders can mimic FA. These include dyskeratosis congenital, Shwachman-Diamond syndrome, and congenital amegakaryocytic thrombocytopenia (Teo, 2008). These disorders will not typically have a positive chromosomal breakage test, but if the breakage test is not definitive, then it may be difficult to distinguish between the syndromes on clinical parameters. Genetic testing for these other disorders is also available, targeting mutations that are distinct from those seen in FA.
Treatment recommendations based on expert consensus were published in 2008, sponsored by the Fanconi Anemia Research Fund (Fanconi Anemia Research Fund, 2008). For bone marrow failure, this document recommends monitoring for mild bone marrow failure and hematopoietic stem-cell transplantation (HSCT) for moderate to severe bone marrow failure. Androgen therapy and/or hematopoietic growth factors are treatment options if HSCT is unavailable or if the patient declines transplantation. FA patients have increased sensitivity to the conditioning regimens used for HSCT, and as a result, reduced intensity regimens are used. Because of this different treatment approach, it is crucial to confirm or exclude a diagnosis of FA before HSCT.
Genetics of FA
FA is an inherited disorder, with most transmission (>99%) occurring by the autosomal recessive route, with a very small number of mutations that are X-linked. The carrier frequency is approximately 1 in 300 in the general populations and an increased carrier frequency of approximately 1 in 100 for certain populations such as Ashkenazi Jews and South African Afrikaners.
Molecular genetic testing is complicated by the presence of at least 15 genes. For all the known genes associated with FA sequence, analysis is complicated by the number of genes to be analyzed, the large number of possible mutations in each gene, the presence of large insertions or deletions in some genes and the size of many of the FA-related genes. If the complementation group has been established, the responsible mutation can be determined by sequencing of the corresponding gene (Alter, 2013). Genes associated with Fanconi Anemia include: FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C and SLX4.
Genetic testing for FA is a complex process that involves multiple steps and a number of different potential approaches. Most of the testing procedures described in the literature involve a combination of PCR [polymerase chain reaction], direct sequencing, and next generation sequencing to identify a full complement of mutations associated with FA (Ameziane, 2008; Chandrasekharappa, 2013; Zhang, 2014).
However, in clinical care, a more directed approach can be taken. In many cases complementation groups testing will have been performed prior to genetic testing and this will direct genetic testing to 1 of the 15 known genes associated with FA. Direct sequencing and/or deletion/duplication analysis of these few genes may be the most accurate and efficient approach in many cases.
In the absence of complementation testing, the greatest yield will be in testing for FANCA, followed by FANCC and FANCG. If a patient with Fanconi anemia is negative for mutations in these genes, then testing for many low-frequency mutations may be necessary. Next generation sequencing offers considerable advantages in testing multiple genes simultaneously for patients in this situation.
Regulatory Status
No U.S. Food and Drug Administration-cleared genetic tests for FA were found. Thus, these tests are offered as laboratory-developed tests. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
There is a specific CPT code for FANCC common variant testing:
81242 FANCC (Fanconi anemia, complementation group C)(eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4a>T)
Other testing for FA could be reported with the unlisted molecular pathology code 81479.
Related policies:
Policy # 1998057  Amniocentesis and/or Chorionic Villus Sampling to Detect Fetal Hereditary or Chromosomal Abnormalitites
Policy # 2005021  Preimplantation Genetic Diagnosis, Testing or Treatment

Genetic Testing has contract limitations in most member benefit certificates of coverage. Carrier testing is a contract exclusion in most member benefit certificates of coverage. Preimplantation genetic testing and fetal testing in utero are addressed in separate coverage policies.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for the diagnosis of Fanconi anemia meets member benefit certificate primary coverage criteria when the following criteria are met:
    • Clinical signs and symptoms of Fanconi anemia are present; AND
    • A definitive diagnosis of Fanconi anemia cannot be made after standard workup, ie, nondiagnostic results on chromosome breakage analysis
Genetic testing of asymptomatic individuals to determine future risk of disease meets member benefit certificate primary coverage criteria when there is a first-degree relative with a documented diagnosis of Fanconi anemia.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for Fanconi anemia in any situation other than those listed above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for Fanconi anemia in any situation other than those listed above is considered not medically necessary. Services that are not medically necessary are specific contract exclusions in most member benefit certificates of coverage.

The evaluation of a genetic test focuses on 3 main principles: (1) analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); (2) clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and (3) clinical utility (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).
Analytic Validity
Commercially available genetic testing for Fanconi anemia (FA) involves a variety of methods such as chip-based oligonucleotide hybridization, polymerase chain reaction (PCR), direct sequencing of proteincoding portions, and flanking regions of targeted exons, and next-generation sequencing. The analytic validity is highest for direct sequencing, approaching 100%. For other methods of genetic testing, the analytic validity may be lower and less precisely defined. For genomic hybridization and next-generation sequencing, the analytic sensitivity is in the range of 95% to 99%.
Clinical Validity
There is limited published data on the clinical validity of genetic testing for FA. The evidence reviewed here is for some of the larger cohorts of FA patients described in the literature, with emphasis on more recent publications, because earlier publications may not reflect the current spectrum of mutations that are currently known.
The International Fanconi Anemia Registry (IFAR) is a registry of FA patients that has been maintained since 1982 at Rockefeller University. Several publications from this registry provide information on clinical validity (Auerback, 2003; Levran, 2005; Levran, 1997). However, these publications tend to be mutation-specific, thereby providing information on clinical validity for that mutation alone. For example, Levran et al published an analysis of the spectrum of FANCA mutations in patients enrolled in the IFAR (Levran, 2005). These authors reported that the detection rate for FANCA mutations (clinical sensitivity) in 181 patients in the registry was 55% (Levran, 2005). A similar study analyzing the FANCG gene reported that pathogenic mutations were identified in 9% (Auerbach, 2003).
In 2014, De Rocco et al published the results of mutation analysis on 100 unrelated patients with FA, most of whom were of Italian ancestry (De Rocco, 2014).  All patients had a clinical diagnosis of FA and approximately half (48/100) had complementation group analysis to direct candidate gene selection, an algorithm of genetic testing that used a combination of direct sequencing, multiplex ligation-dependent probe amplification (MPLA), and next-generation sequencing.
A total of 108 mutations were identified that were potentially pathogenic, with all patients having at least 1 mutation identified and some patients having more than one. The most common involved genes were FANCA (79%), FANCG (8%), FANCC (3%), FANCD2 (2%), and FANCB (1%). Of the 108 mutations, 62 had been previously identified as associated with FA, and the remaining 46 were novel mutations. For the novel mutations, large deletions or duplications were considered to be clearly pathogenic, but point mutations could not always be determined as definitely pathogenic. For example, of the 85 mutations in the FANCA gene, 22% were point mutations that were classified as variants of unknown significance.
In a cohort of 80 patients from The Netherlands who were referred for genetic testing after a confirmed diagnosis of FA, a genetic mutation was identified in 73 patients (91%) (Ameziane, 2008).  All patients underwent comprehensive mutation analysis that consisted of PCR, MPLA, and next-generation sequencing. There were 92 distinct mutations detected in 73 patients, 56 of which were novel mutations. Mutations were most common in the genes FANCA (63%), FANCC (10%), and FANCG (7%).
Clinical Utility
No studies were identified that directly evaluated clinical utility.
The diagnosis of FA can usually be made on the basis of clinical presentation and chromosome breakage analysis. In these cases, genetic testing is not required to confirm the diagnosis. In a minority of cases, the chromosome breakage analysis is not conclusive, and the diagnosis cannot be made with certainty. In those situations, genetic testing can confirm the diagnosis of FA if a known pathologic mutation is found. Genetic testing can also distinguish FA from related causes of bone marrow failure, in which mutations distinct from those associated with FA are found.
Testing of Asymptomatic Individuals
Early identification of asymptomatic patients may improve outcomes by instituting treatment of early bone marrow failure that may delay or prevent the progression to complete failure. Outcomes of hematopoietic stem-cell transplantation (HSCT) are likely to be optimal when patients have bone marrow failure, but do not have severe, debilitating disease and have not yet developed complications of severe disease such as opportunistic infections. Therefore, testing of asymptomatic individuals who have a first-degree relative with a diagnosis of FA is likely to result in improved outcomes.
Summary of Evidence
There is limited published evidence available to determine whether genetic testing for Fanconi anemia (FA) improves outcomes. The disease is rare and only small cohorts of patients are available to be studied. The available evidence demonstrates that most patients with a clinical diagnosis of FA have pathogenic mutations identified. This supports the use of genetic testing for the diagnosis of FA when standard testing, including chromosomal breakage analysis, is inconclusive. Therefore, genetic testing for FA may be considered medically necessary for diagnosis, when signs and/or symptoms of FA are present, but the diagnosis cannot be made by standard testing.
Testing of an asymptomatic individual to determine future risk of disease has clinical utility if there is a first-degree relative with FA. This will primarily apply to young siblings of an affected individual and may help to direct early monitoring and treatment of bone marrow failure that may prevent or delay progression.
The test also has clinical utility for use in reproductive testing. FA is a severe disorder with limited life expectancy, thus warranting consideration for carrier testing, fetal testing, and preimplantation genetic testing. In these situations, testing of selected individuals is likely to reduce the likelihood of having an affected offspring, and therefore health outcomes are improved. Therefore, carrier testing, fetal testing and preimplantation genetic testing may be considered medically necessary when criteria are met.
Practice Guidelines and Position Statements
The Fanconi Anemia Research Foundation issued 2008 guidelines (Fanconi Anemia Research Foundation, 2008) on diagnosis and management of the disease. The guidelines provide the following information on genetic testing:
Mutation analysis identifies the specific gene changes that lead to FA. Mutation analysis is used to confirm the initial complementation group result, to perform other genetic tests such as carrier testing, prenatal testing, and preimplantation genetic diagnosis and, in some cases, to direct medical care and/or enroll in specific research studies.
Complementation group testing is used to classify individuals with FA according to the specific gene defect causing chromosomal instability. For some patients, complementation group testing will not be possible due to these sample limitations. Furthermore, complementation group testing can currently classify patients into 8 of the 13 known complementation groups.
The American College of Obstetricians and Gynecologist issued a 2009 Committee Opinion on carrier screening for genetic diseases in individuals of Eastern European and Jewish descent (ACOG, 2009). The opinion made the following 7 recommendations:
1. The family history of individuals considering pregnancy, or who are already pregnant, should determine whether either member of the couple is of Eastern European (Ashkenazi) Jewish ancestry or has a relative with one or more of the genetic conditions listed in Table 1.
2. Carrier screening for TSD [Tay-Sachs disease], Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals before conception or during early pregnancy so that a couple has an opportunity to consider prenatal diagnostic testing options. If the woman is already pregnant, it may be necessary to screen both partners simultaneously so that the results are obtained in a timely fashion to ensure that prenatal diagnostic testing is an option.
3. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease. Patient education materials can be made available so that interested patients can make an informed decision about having additional screening tests. Some patients may benefit from genetic counseling.
4. When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals is unknown for all of these disorders, except for TSD and cystic fibrosis. Therefore, it is difficult to accurately predict the couple's risk of having a child with the disorder.
5. Individuals with a positive family history of one of these disorders should be offered carrier screening for the specific disorder and may benefit from genetic counseling.
6. When both partners are carriers of one of these disorders, they should be referred for genetic counseling and offered prenatal diagnosis. Carrier couples should be informed of the disease manifestations, range of severity, and available treatment options. Prenatal diagnosis by DNA-based testing can be performed on cells obtained by chorionic villus sampling and amniocentesis.
7. When an individual is found to be a carrier, his or her relatives are at risk for carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The provider does not need to contact these relatives because there is no provider–patient relationship with the relatives, and confidentiality must be maintained.
2016 Update
A literature search conducted through March 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted through April 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2018. No new literature was identified that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through April 2019.  There was no new information identified that would prompt a change in the coverage statement.  
2020 Update
A literature search was conducted through April 2020.  There was no new information identified that would prompt a change in the coverage statement.  
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.

81242FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T)
81441Inherited bone marrow failure syndromes (eg, Fanconi anemia, dyskeratosis congenita, DiamondBlackfan anemia, Shwachman-Diamond syndrome, GATA2 deficiency syndrome, congenital amegakaryocytic thrombocytopenia) panel, must include sequencing of at least 30
81479Unlisted molecular pathology procedure

References: Fanconi Anemia Research Foundation.(2008) Fanconi Anemia: Guideline for diagnosis and management. 2008; Accessed August 27, 2014.

Alter BP, MD, MPH, FAAP, Kupfer G, MD.(2013) Fanconi Anemia. Accessed August 27, 2014.

American College of Obstetricians and Gynecologists (ACOG).(2009) Committee Opinion: Carrier screening for genetic diseases in individuals of Eastern European and Jewish descent. 2009; Accessed May 04, 2015.

Ameziane N, Errami A, Leveille F, et al.(2008) Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. Jan 2008;29(1):159-166. PMID 17924555

ARUP Laboratories. Laboratory Test Directory - Chromosome Analysis - Breakage, Fanconi Anemia. Accessed October 22, 2014.

Auerbach AD, Greenbaum J, Pujara K, et al.(2003) Spectrum of sequence variation in the FANCG gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. Feb 2003;21(2):158-168. PMID 12552564

Chandrasekharappa SC, Lach FP, Kimble DC, et al.(2013) Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. May 30 2013;121(22):e138-148. PMID 23613520

De Rocco D, Bottega R, Cappelli E, et al.(2014) Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology. Haematologica. Jun 2014;99(6):1022-1031. PMID 24584348

Fanconi Anemia Research Fund. Guidelines for Diagnosis and Management. 2008; Accessed October 21, 2014.

Khincha PP, Savage SA.(2013) Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol. Oct 2013;50(4):333-347. PMID 24246701

Kutler DI, Singh B, Satagopan J, et al.(2003) A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. Feb 15 2003;101(4):1249-1256. PMID 12393516

Levran O, Diotti R, Pujara K, et al.(2005) Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. Feb 2005;25(2):142-149. PMID 15643609

Levran O, Erlich T, Magdalena N, et al.(1997) Sequence variation in the Fanconi anemia gene FAA Proc Natl Acad Sci U S A. Nov 25 1997;94(24):13051-13056. PMID 9371798

Sakaguchi H, Nakanishi K, Kojima S.(2013) Inherited bone marrow failure syndromes in 2012. Int J Hematol. Jan 2013;97(1):20-29. PMID 23271412

Shimamura A, Alter BP.(2010) Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. May 2010;24(3):101-122. PMID 20417588

Teo JT, Klaassen R, Fernandez CV, et al.(2008) Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes. Pediatrics. Jul 2008;122(1):e139-148. PMID 18595958

Zhang MY, Keel SB, Walsh T, et al.(2014) Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica. Sep 19 2014. PMID 25239263

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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