Genetic Testing for Li-Fraumeni Syndrome

POLICY NUMBER

A.2.04.101

DESCRIPTION

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several types of tumors. The syndrome is caused by germline pathogenic variants in the TP53 gene. Testing for LFS pathogenic variants may be useful in confirming the diagnosis of LFS and/or evaluating genetic status in asymptomatic relatives of an index case.

TP53 Gene

The TP53 gene contains the genetic instructions for the production of tumor protein p53. The p53 protein is a tumor suppressor that functions as a cell cycle regulator to prevent cells from uncontrolled growth and division when there is DNA damage. Somatic (acquired) pathogenic variants are one of the most frequent alterations found in human cancers. Germline (inherited) pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS).

Li-Fraumeni Syndrome

Li-Fraumeni syndrome is a cancer predisposition syndrome associated with a high lifetime cumulative risk of cancer and a tendency for multiple cancers in affected individuals. The syndrome was originally described based on a retrospective analysis of families with aggressive soft tissue sarcomas in young siblings and their biologically related cousins.

The tumor types most closely associated with LFS include premenopausal breast cancer, bone and soft tissue sarcomas, central nervous system (CNS) tumor, adrenocortical carcinoma, hypodiploid acute lymphoblastic leukemia, unusually early onset of other adenocarcinomas, or other childhood cancers. Sarcoma, breast cancer, adrenocortical tumors, and certain brain tumors have been referred to as the “core” cancers of LFS since they account for the majority of cancers observed in individuals with germline TP53 pathogenic and likely pathogenic variants. Other malignancies associated with LFS include a wide variety of gastrointestinal tract, lung, skin, and thyroid cancers as well as leukemias and lymphomas.

Individuals with LFS are at increased risk of developing multiple primary tumors, with subsequent malignancies, not all being clearly related to the treatment of the previous neoplasms. The risk of developing a second tumor has been estimated at 40% to 49%. In a study of 322 pathogenic variant carriers from France, 43% of individuals had multiple malignancies.

Individuals with LFS are at increased risk of both bone and soft tissue sarcomas. Sarcomas of various histologies account for 25% of the cancers reported in people with LFS, with the most commonly reported sarcomas in an international database being rhabdomyosarcoma before age 5 years and osteosarcoma at any age. Women with LFS are at greatly increased risk of developing premenopausal breast cancer, with the median age of diagnosis being 33 years of age. Male breast cancer has rarely been reported in LFS families. Many types of brain tumors have been described in LFS, including astrocytomas, glioblastomas, medulloblastomas, and choroid plexus carcinomas. The median age of onset of LFS-related brain tumors is 16 years of age. Individuals with LFS are at increased risk of developing adrenocortical carcinoma. For adults, in one series, it was estimated that 6% of individuals diagnosed with adrenocortical carcinoma after age 18 years have a germline TP53 pathogenic variant.

Data from M.D. Anderson Cancer Center’s long-term clinical studies of LFS have shown that the risk of developing soft tissue sarcomas is greatest before the age of 10 years, brain cancer appears to occur early in childhood with a smaller peak in risk in the fourth to fifth decade of life, risk for osteosarcoma is highest during adolescence, and breast cancer risk among females with LFS starts to increase significantly around age 20 and continues into older adulthood.

Clinical Diagnosis

The diagnosis of LFS is based on an evolving set of clinical classification criteria, established using salient aspects of family history and tumor-related characteristics. The first formal criteria, the classic LFS criteria, were developed in 1988, and are the most stringent used to make a clinical diagnosis of LFS.

Classic Li-Fraumeni Syndrome

Classic LFS is defined by the presence of all of the following criteria:

• A proband with a sarcoma before 45 years of age,

• A first-degree relative with any cancer before 45 years of age, and

• A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age.

Chompret Criteria

Chompret and colleagues developed criteria that have the highest positive predictive value, and that, when combined with the classic LFS criteria, provide the highest sensitivity for identifying individuals with LFS. The Chompret criteria were updated in 2009 to assist in identifying families with milder phenotypes. The Chompret criteria will also identify individuals with de novo TP53 pathogenic variants, whereas the classic LFS criteria require a family history.

The Chompret criteria, most recently updated in 2015, are defined as the following:

• Proband with tumor belonging to the LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma) before age 46 years AND at least one, first- or second-degree relative with LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; or

• Proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; or

• Patient with adrenocortical carcinoma, rhabdomyosarcoma of embryonal anaplastic subtype, or choroid plexus tumor, irrespective of family history; or

• Female proband with breast cancer before age 31 years.

National Comprehensive Cancer Network guidelines recommend TP53 testing for individuals who meet classic LFS criteria and Chompret criteria.

Molecular Diagnosis

Li-Fraumeni syndrome is associated with germline pathogenic variants in the TP53 gene (chromosome 17p13.1), which encodes for a ubiquitous transcription factor that is responsible for a complex set of regulatory functions that promote DNA repair and tumor suppression. TP53 is the only gene in which pathogenic variants are known to cause LFS, and no other inherited phenotypes are associated specifically with germline pathogenic variants involving TP53. The presence of a TP53 variant is considered diagnostic.

Li-Fraumeni syndrome is a highly penetrant cancer syndrome, with the risks for cancer being about 80% by age 70 years. It is inherited in an autosomal dominant manner. De novo germline TP53 pathogenic variants (no pathogenic variant is identified in either biologic parent) are estimated to be 7% to 20%.

Approximately 95% of pathogenic variants detected in the TP53 gene are sequence variants (small intragenic deletions and insertions and missense, nonsense, and splice site variants). Large deletions and duplications not readily detected by sequence analysis account for approximately 1% of the pathogenic variants detected.

Certain genotype-phenotype correlations have been reported in families with LFS and TP53 pathogenic variants. Genotype-phenotype correlations in LFS are predictive of the age of onset of a tumor, level of risk of developing a tumor, and outcome in patients with TP53 germline pathogenic variants.

Management

TreatmentThe evaluation of cancer in an individual diagnosed with LFS should be based on personal medical history and, to some degree, the specific pattern of cancer in the family. Women with LFS who develop breast cancer are encouraged to consider bilateral mastectomies to reduce the risk of developing a second primary breast cancer and to avoid exposure to radiotherapy. Preventive measures may include risk-reducing (prophylactic) mastectomy in women, and in all patients with a TP53 pathogenic variant, avoidance of radiotherapy, because the evidence has suggested that TP53 pathogenic variants confer an increased sensitivity to ionizing radiation and the possibility of radiation-induced malignancies.

Surveillance Li-Fraumeni syndrome confers a high risk of multiple different types of cancer, which poses challenges for establishing a comprehensive screening regimen, and many of the cancers associated with LFS do not lend themselves to early detection. There is no international consensus on the appropriate clinical surveillance strategy in individuals with LFS, but, in general, the strategy includes physical examination, colonoscopy, and breast imaging. Other protocols being evaluated include additional imaging techniques and biochemical assessment. The National Comprehensive Cancer Network has consensus-based screening guidelines.

Testing Strategy

Given the common germline TP53 variant types associated with LFS, a possible testing strategy to optimize yield would be:

1. Sequencing of the entire TP53 coding region (exons 2 through 11). Examples of types of pathogenic variants detected by sequence analysis include small insertions and deletions (frameshift), and missense, nonsense, and splice site variants; most are missense variants.

2. Deletion and duplication analysis, which detects large deletions and duplications involving the coding region (exon 1) or promoter; these types of deletions and duplications are not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. These types of pathogenic variants account for less than 1% of those found in individuals with LFS.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Genetic testing for TP53 may be considered medically necessary to confirm a diagnosis of Li-Fraumeni syndrome under the following conditions:

• In an individual who meets either the classic or the Chompret clinical diagnostic criteria for Li-Fraumeni syndrome, or

• In individuals with early-onset breast cancer (age of diagnosis <31 years), or

• In pediatric hypodiploid acute lymphoblastic leukemia (see Policy Guidelines).

Targeted TP53 familial variant testing may be considered medically necessary in an at-risk relative of a proband with a known TP53 pathogenic variant.

Genetic testing for a germline TP53 variant is considered investigational for all other indications (see Policy Guidelines).

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The NCCN Pediatric Acute Lymphoblastic Leukemia panel considers “pediatric” to include any individual age ≤18 years, as well as adolescent and young adult (AYA) individuals >18 years treated in a pediatric oncology setting; the latter could include individuals up to age 30 years.

This policy addresses germline testing for TP53 and does not address somatic testing. Somatic TP53 variants found on tumor testing are common across many types of cancers. According to the National Comprehensive Cancer Network (NCCN), the finding of somatic TP53 variant(s) on tumor testing would support genetic counseling for assessment of risk for germline alterations associated with Li-Fraumeni Syndrome.

Genetics Nomenclature Update

The Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization (HUGO), and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/17/2014: Approved by Medical Policy Advisory Committee.

12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81405.

08/25/2015: Medical policy revised to add ICD-10 codes.

09/22/2015: Policy description updated to change "radiation therapy" to "radiotherapy." Policy statement unchanged. Policy Guidelines section updated to add medically necessary and investigative definitions.

06/07/2016: Policy number A.2.04.101 added.

08/22/2016: Policy description updated. Policy statements unchanged. Policy Guidelines updated to add genetic counseling information.

06/27/2017: Code Reference section updated to revise code description for CPT code 81405, effective 07/01/2017.

08/18/2017: Policy terminology updated to change "mutations" to "pathogenic variants" throughout policy. Policy description updated regarding the TP53 gene. Medically necessary statement criteria regarding women with early-onset breast cancer updated to change the age of diagnosis from "≤35 years" to "<31 years" to align with the NCCN age cutoff. Second medically necessary statement updated to change "Genetic testing" to "Targeted." Policy Guidelines updated regarding standard terminology for variant classification and to remove the diagnostic criteria for LFS, as it is listed in the policy description.

12/22/2017: Code Reference section updated to revise description for CPT code 81405 effective 01/01/2018.

08/07/2018: Policy description updated regarding LFS testing strategy. Second medically necessary statement updated to change "Targeted TP53 familial variant" to "Targeted TP53 familial variant testing." Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

08/13/2019: Policy reviewed; no changes.

08/17/2020: Policy reviewed; no changes.

12/16/2020: Code Reference section updated to add new CPT codes 81351, 81352, and 81353, effective 01/01/2021.

08/30/2021: Policy description updated regarding tumor types associated with Li-Fraumeni Syndrome and the Chompret criteria. Policy statements unchanged. Policy Guidelines updated regarding somatic TP53 variants and to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

08/30/2022: Policy description updated. Policy statements updated to change "patient" to "individual." Policy Guidelines updated regarding genetic counseling.

03/15/2024: Policy description updated regarding tumor types associated with Li-Fraumeni Syndrome. Policy statement updated to add that genetic testing for TP53 may be considered medically necessary to confirm a diagnosis of Li-Fraumeni syndrome in pediatric hypodiploid acute lymphoblastic leukemia (see Policy Guidelines). Policy statement updated to change "not medically necessary" to "investigational." Policy Guidelines updated regarding terminology. Code Reference section updated to remove CPT code 81405 and add ICD-10 diagnosis codes C91.00 - C91.02.

08/12/2024: Policy reviewed. Policy statements unchanged. Policy Guidelines updated with minor changes.

08/28/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.101

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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