Skip to main content

Genetic Testing for Li Fraumeni Syndrome AHS – M2081

Commercial Medical Policy
Origination: 01/2019
Last Review: 01/2019

Description of Procedure or Service

Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome characterized by a wide range of malignancies that appear at an unusually early age generally associated with defects in the tumor protein p53 gene (TP53) (Evans, 2017; Mai et al., 2016; Malkin, 2011).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage genetic testing for Li-Fraumeni syndrome for when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Li-Fraumeni Syndrome is covered

  1. Genetic counseling for Li-Fraumeni Syndrome genetic testing is considered medically necessary.
  2. Genetic testing for TP53 mutations is considered medically necessary to confirm a diagnosis of Li-Fraumeni syndrome under the following conditions:
    1. In a patient who meets either the classic or the Chompret clinical diagnostic criteria for Li-Fraumeni syndrome
      1. Classic LFS is defined by the presence of all of the following criteria:
        1.  A proband with a sarcoma before 45 years of age
        2. A first-degree relative with any cancer before 45 years of age
        3. A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age
      2. Chompret clinical diagnostic criteria is defined by one of the following:
        1. Proband with tumor belonging to LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least 1 first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors at any age; OR
        2. Proband with multiple tumors (except multiple breast tumors), 2 of which belong to LFS tumor spectrum and the first of which occurred before age 46 years; OR
        3. Patient with adrenocortical carcinoma (ACC) or choroid plexus tumor, at any age irrespective of family history
    2.  In women with early onset breast cancer (diagnosed at ≤30 years). The optimal strategy for confirming a TP53 mutation in a proband would be:
      1.  Sequencing of the entire TP53 coding region (exons 2-11). If sequencing is negative, then:
      2.  Deletion/duplication analysis
  3. Genetic testing for a TP53 mutation is considered medically necessary in a first, second or third degree relative of a proband with a known TP53 mutation (see Policy Guidelines No. 1). 
  4. Comprehensive genetic testing for a TP53 mutation (i.e. full sequencing of the genes and detection of large gene rearrangements) or multi-gene testing is considered medically necessary in a patient or, if unaffected, family member with highest likelihood of a mutation if there is no known familial TP53 mutation.

When Genetic Testing for Li-Fraumeni Syndrome is not covered

Genetic testing for a germline TP53 mutation is considered investigational.

Policy Guidelines

Policy Guideline #1:

At the present time, there are no specific, evidence-based, standardized guidelines for recommendations of which “at risk” relatives should be tested. In relatives of an index case, the risk of having a pathologic mutation, and developing disease, is influenced by numerous factors that should be considered in evaluating risk:

  1. Proximity of relation to index case (first-, second-, or third degree)
  2. Mode of inheritance of mutation (autosomal dominant versus autosomal recessive)
  3. Degree of penetrance of mutation (high, intermediate or low)
  4. Results of detailed pedigree analysis
  5. De novo mutation rate

If a proband has a TP53 mutation, the risk to the proband’s offspring of inheriting the mutation is 50 percent. If a proband has a TP53 mutation, the risk to other relatives may depend on the genetic status of the proband’s parents (that is, it is not a de novo mutation in the proband). Most TP53 mutations are inherited from 1 of a proband’s parents. After a mutation has been identified in a proband, the proband’s parent with any pertinent cancer history of family history should be tested first to establish the lineage of the mutation; otherwise, both parents should be tested. A family history could appear to be negative because of incomplete penetrance of the mutation, limited family members available for testing, early death of a parent, etc.

Literature Review

Li-Fraumeni syndrome is a rare cancer predisposition syndrome associated with germline mutation in the tumour suppressor gene TP53 on chromosome 17p13(Correa, 2016). It has an autosomal dominant pattern of inheritance with high penetrance. The human TP53 gene (chromosome 17p13.1) encodes for a ubiquitous transcription factor that is responsible for a complex set of critical regulatory functions that promote DNA repair and tumor suppression during episodes of cellular stress and DNA damage(Sorrell, Espenschied, Culver, & Weitzel, 2013). Most TP53 mutations are clustered in the DNA-binding domain within specific codons, such as 175 and 248(Villani et al., 2016). TP53 mutations are often missense alterations(Petitjean et al., 2007) that cause a change in one nucleotide and encode for a different amino acid than the one typically found in that particular location within the protein. Missense mutations are usually transcriptionally inactive leading to downstream events permissive for development of various malignancies throughout life; however, some reports have shown gain of function oncogenic effects in TP53 ( Brosh & Rotter, 2009; Sigal & Rotter, 2000).

These patients have a very high lifetime cumulative risk of developing malignancies and earlyonset malignancies. Around 50% of the individuals carrying mutations in TP53 will develop cancer by the age of 30 years(Hwang, Lozano, Amos, & Strong, 2003; Lustbader, Williams, Bondy, Strom, & Strong, 1992; Schneider, Zelley, Nichols, & Garber, 2013a), with a lifetime risk of up to 70% in men and almost 100% in women(Chompret et al., 2000). While many tumor types can be seen in patients with LFS, four cancers (breast, sarcoma, brain, and adrenocortical carcinoma) make up about 80% of LFS associated tumors (Gonzalez et al., 2009; Li et al., 1988; Lynch, Mulcahy, Harris, Guirgis, & Lynch, 1978; Olivier et al., 2003).

Breast Cancer accounts for about 25-30% of all LFS-associated tumors (Gonzalez et al., 2009; Olivier et al., 2003). Women with LFS-associated breast cancer tend to present at an earlier age (in the 20s or early 30s) with more advanced stage disease at the time of initial diagnosis.

Sarcomas account for another 25-30% of all LFS-associated tumor (Gonzalez et al., 2009; Ognjanovic, Olivier, Bergemann, & Hainaut, 2012; Olivier et al., 2003; Palmero, Achatz, AshtonProlla, Olivier, & Hainaut, 2010). Multiple types of soft tissue sarcomas and osteosarcoma are associated with LFS; but Ewing’s sarcoma, gastrointestinal stromal cell tumors (GIST), desmoids tumors, and angiosarcomas have not been reported in LFS (Olivier et al., 2003).

Brain Tumors occur in 9-16% of individuals with TP53 mutations (Gonzalez et al., 2009; Olivier et al., 2003; Palmero et al., 2010; Ruijs et al., 2010) Glioblastomas/astrocytomas are the most common but, medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and choroid plexus tumors may also be seen (Farrell & Plotkin, 2007; Ruijs et al., 2010).

Adrenocortical Carcinoma (ACC) accounts for 10-14% of cancers in TP53 mutation carriers overall (Gonzalez et al., 2009; Palmero et al., 2010). While ACC has been diagnosed in individuals with LFS at a wide range of ages, it is considered a hallmark of LFS when diagnosed in childhood (Gonzalez et al., 2009; Herrmann et al., 2012; Palmero et al., 2010).

Other LFS Cancers

Beyond the four core LFS cancers, the next most frequently associated cancers include leukemia, lung, colorectal, skin, gastric, and ovarian (Gonzalez et al., 2009; Masciari et al., 2011; Olivier et al., 2003; Palmero et al., 2010; Walsh et al., 2011; Wong et al., 2006). All cancer types are diagnosed at younger than average ages.

LFS is characterized clinically by the development of cancers arising in multiple organ systems, often at a young age (Birch et al., 1998; Birch et al., 1994; Garber et al., 1991; Li et al., 1988; Mai et al., 2012; Malkin et al., 1990; Olivier, Hollstein, & Hainaut, 2010; Ruijs et al., 2010). The classic phenotype was clinically defined before the identification of germline mutations in TP53; these criteria are the most stringent and are the ones used to make a clinical diagnosis of LFS (with or without the identification of a deleterious germline TP53 mutation)(Li et al., 1988). Further studies revealed that, although highly specific for TP53 germline mutations, these criteria fail to include many mutation-positive families. Broader criteria were developed by Birch and Eeles to identify families which are Li-Fraumeni-like (LFL)(Birch et al., 1994; Eeles, 1995). The most robust analysis of TP53 mutation carriers to this date was performed in France by Bougeard et al., in developing the most recent version of the Chompret criteria to better identify families with milder phenotypes(Chompret et al., 2001; Gonzalez et al., 2009) shown to provide the highest positive predictive value and, when combined with the classic LFS criteria, provided the highest sensitivity for identifying individuals with LFS(Bougeard et al., 2008; Tinat et al., 2009).

Clinical criteriaDescription
Classical LFS (Li,
Fraumeni et al.,
1988)		I-sarcoma diagnosed in childhood/young adulthood (≤ 45 years) and
II-first-degree relative with any cancer in young adulthood (≤ 45 years) and
III-first- or second-degree relative with any cancer diagnosed in young adulthood (≤ 45 years) or sarcoma diagnosed at any age.
LFL – Birch (Birch,
Hartley et al., 1994)		I-childhood cancer (at any age) or sarcoma, CNS tumor, or ACC in young adulthood (≤ 45 years) and
II-first- or second-degree relative with LFS-spectrum cancer (sarcoma, BC, CNS tumor, ACC, leukemia) at any age and
III-first- or second-degree relative with any cancer diagnosed at age < 60 years.
LFL – Eeles 1 (Eeles, 1995) Eeles 2 (Eeles, 1995)I-at least 2 first- or second-degree relatives with LFS-spectrum cancer (sarcoma, BC, CNS tumor, ACC, leukemia, melanoma, prostate cancer, pancreatic cancer) diagnosed at any age I-sarcoma diagnosed at any age and II-at least 2 other tumors diagnosed in one or more first- or second-degree relatives: BC at age < 50 years; CNS tumor, leukemia, ACC, melanoma, prostate cancer, pancreatic cancer at age < 60 years; or sarcoma at any age.
LFL – Chompret (Frebourg, Abel et al., 2001)I-diagnosis of sarcoma, CNS tumor, BC, ACC at age < 36 years and II-first- or second-degree relative with any of the above cancers (except BC if proband had BC) or relative with multiple primary tumors at any age or III-multiple primary tumors, including two of the following: sarcoma, CNS tumor, BC, or ACC, with the first tumor diagnosed at age < 36 years regardless of family history; or IV-ACC at any age, regardless of family history.
LFL – Modified Chompret (Bougeard, Sesboüé et al., 2008; Tinat, Bougeard et al., 2009)I-index case with LFS-spectrum cancer (sarcoma, BC, CNS tumor, ACC, leukemia, bronchioloalveolar carcinoma) occurring at age < 46 years and II-a first- or second-degree relative with LFS-spectrum cancer occurring at age < 56 years (except BC if the index case has BC as well), or multiple tumors; or III-index patient with multiple tumors, at least two of which are in the LFS spectrum, the first occurring at age < 46 years; or IV-ACC or choroid plexus carcinoma occurring at any age or BC occurring at age < 36 years without BRCA1orBRCA2mutations

ACC: adrenocortical carcinoma; BC: breast cancer; CNS: central nervous system; LFS: LiFraumeni syndrome; LFL: Li-Fraumeni-like syndrome.

Siblings and offspring of the proband should be tested. If one of the proband’s parents carries the TP53mutation, each sibling has a 50% risk of having the mutation. If neither parent is found to carry the mutation, the risk to siblings is low, but they should be tested due to the possibility of germline mosaicism. Offspring of a proband have a 50% risk of carrying the mutation (Ballinger, Mitchell, & Thomas, 2015).Phenotypes of families carrying TP53 mutations can be highly variable (Malkin, 2011; McBride et al., 2014). Additionally, mutations in TP53 can lead to different consequences on gene function (McBride et al., 2014). The possibility of a second locus involved in LFS is an additional issue in the etiology of the syndrome, since approximately 20 % of LFS and up to 80 % of LFL families do not exhibit TP53 mutations (Malkin, 2011; McBride et al., 2014). However no association was found with p53 partners in tumor suppressor pathways, BAX(Barlow et al., 2004), CDKN2A(Portwine, Lees, Verselis, Li, & Malkin, 2000), TP63(Bougeard et al., 2001), CHEK2(Bougeard et al., 2001), BCL10(Stone et al., 1999), or PTEN(Brown, Sexsmith, & Malkin, 2000) in TP53-negative families. Although a few studies have linked other loci to LFL (Aury-Landas et al., 2013; Bachinski et al., 2005), TP53 remains the only gene conclusively associated to the syndrome.

Rana et al (2018) compared the personal and family cancer histories of TP53+ carriers who were identified though single gene testing (SGT) versus multi gene panel testing (MGPT). They found that “MGPT TP53+ individuals (n = 126) had an older median age at first cancer than SGT TP53+ carriers (n = 96; women: median = 36 vs 28 years, P < .001; and men: median = 40 vs 15 years, P = .004). The median age of breast cancer diagnosis was 40 years in MGPT TP53+ women vs 33 years in SGT TP53+ women (P < .001). In both cohorts, childhood and LFS core cancers, and for women, multiple primary cancers (not multiple breast tumors), were associated with TP53+ results. Established LFS testing criteria were less often met by MGPT TP53+ individuals.” They concluded that “MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks.”

Clinical Validity and Utility

According to Schneider et al (Schneider, Zelley, Nichols, & Garber, 2013b), approximately 80 percent of families with features of Li-Fraumeni Syndrome will have an identifiable TP53 mutation. Families that have clinical features of LFS without TP53 mutation are more likely to have a different hereditary cancer syndrome.

Some studies have reported that approximately 70% to 80% of families meeting the classic LiFraumeni syndrome criteria have TP53 mutation (Nagy, Sweet, & Eng, 2004; Varley, 2003). However, Gonzalez et al (Gonzalez et al., 2009) reported that a slightly lower positive predictive value for the classic criteria (56%), with high specificity but low sensitivity (40%). Chompret et al (Chompret et al., 2001)reported TP53 mutations can be found in 20% of cases using the Chompret criteria. Gonzalez et al (2009) reported a higher positive predictive value using Chompret criteria (35%).

Gonzalez et al (2009) used a clinical testing cohort to understand the spectrum of tumors associated with germline p53 mutations. Mutations were identified in 17% of patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma. When the classic Li-Fraumeni syndrome and Chompret criteria were used together, the testing sensitivity was 95% and the specificity was 52%.

Villani et al (Villani et al., 2011) assessed the feasibility and clinical impact of a comprehensive surveillance protocol in asymptomatic TP53 mutation carriers in families with Li-Fraumeni syndrome. 33 TP53 mutation carriers were identified, 18 of whom underwent surveillance. The authors reported a 3-year overall survival of 100% in the surveillance group compared to 21% in the non-surveillance group.

In 2016, Villani et al update their assessment of prospective observational study and modified the surveillance protocol. Out of the 89 carriers of TP53 pathogenic variants in 39 unrelated families, 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. The authors reported a 5- year overall survival was 88·8% in the surveillance group and 59·6% in the non-surveillance group (Villani et al., 2016).

Mai et al (2017) determined the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid wholebody magnetic resonance imaging (MRI) and laboratory measurements. They found that “Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers [ductal carcinoma in situ]); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer.”

Federal Applicable Regulations

This test is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Guidelines and Recommendations

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) maintains guidelines for the diagnosis and management of Li-Fraumeni Syndrome (NCCN, 2018). NCCN recommends testing for Li-Fraumeni Syndrome in the following situations:

  • Individual from a family with a known TP53 mutation
  • Classic Li-Fraumeni syndrome criteria
  • Chompret criteria

The NCCN recommendations for management of Li-Fraumeni syndrome in adults include the following:

Breast cancer risk for women:

  • Breast awareness starting at age 18 years
  • Clinical breast exam every 6-12 months, starting at age 20 years
  • Breast screening:
    • Age 20-29 years, annual breast MRI screening with contrast
    • Age >30-75 years, breast MRI screening with contrast and mammogram with consideration of tomosynthesis
    • Age >75 years, management considered on an individual basis.
    • For women with a TP53 mutation, who are treated for breast cancer and who have not had a bilateral mastectomy, screening with annual breast MRI and mammogram should continue as described above
  • Discuss risk-reducing mastectomy and counsel regarding degree of protection, degree of age-specific cancer risk, reconstruction options, and competing risks of other cancers.
  • Address psychosocial, social, and quality-of-life aspects of risk-reducing mastectomy

Other cancer risks:

  • Comprehensive physical exam including neurologic examination with high index of suspicion for rare cancers and second malignancies in cancer survivors every 6-12 months.
  • Colonoscopy and upper endoscopy every 2-5 y starting at age 25 or 5y before the earliest known colon cancer in the family
  • Annual dermatologic evaluation starting at 18 y
  • Annual whole body MRI
  • Annual brain MRI may be performed as part of the whole body MRI or as a separate exam

Reproductive options:

  • For patients of reproductive age, advise about options for prenatal diagnosis and assisted reproduction including pre-implantation genetic diagnosis. Discussion should include known risks, limitations, and benefits of these technologies.

For relatives:

  • Advise about possible inherited cancer risk to relatives, options for risk assessment, and management
  • Recommend genetic counseling and consideration of genetic testing for at-risk relatives

Children:

  • Genetic testing is generally not recommended when results would not impact medical management.
  • For additional information on the management of children with LFA see Kratz C, Achatz M, BrugieresL et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin cancer Res 2017; 23:e38-45 and Greer M, Voss S, States L. Pediatric Cancer Predisposition Imaging: Focus on whole body MRI. Clin Cancer Res 2017; 23: e6-13.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81404, 81405, 81407, 96040, S0265

Code NumberPA RequiredPA Not RequiredNot Covered
81404X  
81405X  
81407X  
96040 X 
S0265 X 

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Aury-Landas, J., Bougeard, G., Castel, H., Hernandez-Vargas, H., Drouet, A., Latouche, J. B., . . . Flaman, J. M. (2013). Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours. Eur J Hum Genet, 21(12), 1369- 1376. doi:10.1038/ejhg.2013.68

Bachinski, L. L., Olufemi, S. E., Zhou, X., Wu, C. C., Yip, L., Shete, S., . . . Krahe, R. (2005). Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res, 65(2), 427-431.

Ballinger, M. L., Mitchell, G., & Thomas, D. M. (2015). Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol, 27(4), 332-337. doi:10.1097/cco.0000000000000200

Barlow, J. W., Mous, M., Wiley, J. C., Varley, J. M., Lozano, G., Strong, L. C., & Malkin, D. (2004). Germ line BAX alterations are infrequent in Li-Fraumeni syndrome. Cancer Epidemiol Biomarkers Prev, 13(8), 1403-1406.

Birch, J. M., Blair, V., Kelsey, A. M., Evans, D. G., Harris, M., Tricker, K. J., & Varley, J. M. (1998). Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene, 17(9), 1061-1068. doi:10.1038/sj.onc.1202033

Birch, J. M., Hartley, A. L., Tricker, K. J., Prosser, J., Condie, A., Kelsey, A. M., . . . et al. (1994). Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res, 54(5), 1298-1304.

Bougeard, G., Limacher, J. M., Martin, C., Charbonnier, F., Killian, A., Delattre, O., . . . Frebourg, T. (2001). Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J Med Genet, 38(4), 253-257.

Bougeard, G., Sesboue, R., Baert-Desurmont, S., Vasseur, S., Martin, C., Tinat, J., . . . French, L. F. S. w. g. (2008). Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet, 45(8), 535-538. doi:10.1136/jmg.2008.057570

Brosh, R., & Rotter, V. (2009). When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer, 9(10), 701-713. doi:10.1038/nrc2693

Brown, L. T., Sexsmith, E., & Malkin, D. (2000). Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing. Cancer Genet Cytogenet, 123(1), 65-68.

Chompret, A., Abel, A., Stoppa-Lyonnet, D., Brugieres, L., Pages, S., Feunteun, J., & Bonaiti-Pellie, C. (2001). Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet, 38(1), 43-47.

Chompret, A., Brugieres, L., Ronsin, M., Gardes, M., Dessarps-Freichey, F., Abel, A., . . . Feunteun, J. (2000). P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer, 82(12), 1932-1937. doi:10.1054/bjoc.2000.1167

Correa, H. (2016). Li-Fraumeni Syndrome. J Pediatr Genet, 5(2), 84-88. doi:10.1055/s-0036-1579759

Eeles, R. A. (1995). Germline mutations in the TP53 gene. Cancer Surv, 25, 101-124.

Evans, D. G. (2017). Li-Fraumeni syndrome - UpToDate. In M. Ross (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/li-fraumenisyndrome?source=search_result&search=li%20fraumeni&selectedTitle=1~37.

Farrell, C. J., & Plotkin, S. R. (2007). Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin, 25(4), 925-946, viii. doi:10.1016/j.ncl.2007.07.008

Garber, J. E., Goldstein, A. M., Kantor, A. F., Dreyfus, M. G., Fraumeni, J. F., Jr., & Li, F. P. (1991). Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res, 51(22), 6094-6097.

Gonzalez, K. D., Noltner, K. A., Buzin, C. H., Gu, D., Wen-Fong, C. Y., Nguyen, V. Q., . . . Weitzel, J. N. (2009). Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol, 27(8), 1250-1256. doi:10.1200/jco.2008.16.6959

Herrmann, L. J., Heinze, B., Fassnacht, M., Willenberg, H. S., Quinkler, M., Reisch, N., . . . Hahner, S. (2012). TP53 germline mutations in adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab, 97(3), E476-485. doi:10.1210/jc.2011-1982

Hwang, S. J., Lozano, G., Amos, C. I., & Strong, L. C. (2003). Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet, 72(4), 975-983. doi:10.1086/374567

Li, F. P., Fraumeni, J. F., Jr., Mulvihill, J. J., Blattner, W. A., Dreyfus, M. G., Tucker, M. A., & Miller, R. W. (1988). A cancer family syndrome in twenty-four kindreds. Cancer Res, 48(18), 5358-5362.

Lustbader, E. D., Williams, W. R., Bondy, M. L., Strom, S., & Strong, L. C. (1992). Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. Am J Hum Genet, 51(2), 344- 356.

Lynch, H. T., Mulcahy, G. M., Harris, R. E., Guirgis, H. A., & Lynch, J. F. (1978). Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer, 41(5), 2055-2064.

Mai, P. L., Best, A. F., Peters, J. A., DeCastro, R. M., Khincha, P. P., Loud, J. T., . . . Savage, S. A. (2016). Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer, 122(23), 3673-3681. doi:10.1002/cncr.30248

Mai, P. L., Khincha, P. P., Loud, J. T., DeCastro, R. M., Bremer, R. C., Peters, J. A., . . . Savage, S. A. (2017). Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort. JAMA Oncol, 3(12), 1640-1645. doi:10.1001/jamaoncol.2017.1350

Mai, P. L., Malkin, D., Garber, J. E., Schiffman, J. D., Weitzel, J. N., Strong, L. C., . . . Savage, S. A. (2012). Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet, 205(10), 479-487. doi:10.1016/j.cancergen.2012.06.008

Malkin, D. (2011). Li-fraumeni syndrome. Genes Cancer, 2(4), 475-484. doi:10.1177/1947601911413466

Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., . . . et al. (1990). Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science, 250(4985), 1233-1238.

Masciari, S., Dewanwala, A., Stoffel, E. M., Lauwers, G. Y., Zheng, H., Achatz, M. I., . . . Syngal, S. (2011). Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med, 13(7), 651-657. doi:10.1097/GIM.0b013e31821628b6

McBride, K. A., Ballinger, M. L., Killick, E., Kirk, J., Tattersall, M. H., Eeles, R. A., . . . Mitchell, G. (2014). Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol, 11(5), 260-271. doi:10.1038/nrclinonc.2014.41

Nagy, R., Sweet, K., & Eng, C. (2004). Highly penetrant hereditary cancer syndromes. Oncogene, 23(38), 6445-6470. doi:10.1038/sj.onc.1207714

NCCN. (2018). NCCN Clinical Practice Guidelines in Oncology; Genetic/Familial High-Risk Assessment: Breast and Ovarian v1.2018. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

Ognjanovic, S., Olivier, M., Bergemann, T. L., & Hainaut, P. (2012). Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer, 118(5), 1387-1396. doi:10.1002/cncr.26390

Olivier, M., Goldgar, D. E., Sodha, N., Ohgaki, H., Kleihues, P., Hainaut, P., & Eeles, R. A. (2003). LiFraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res, 63(20), 6643-6650.

Olivier, M., Hollstein, M., & Hainaut, P. (2010). TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol, 2(1), a001008. doi:10.1101/cshperspect.a001008

Palmero, E. I., Achatz, M. I., Ashton-Prolla, P., Olivier, M., & Hainaut, P. (2010). Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome. Curr Opin Oncol, 22(1), 64-69. doi:10.1097/CCO.0b013e328333bf00

Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S. V., Hainaut, P., & Olivier, M. (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat, 28(6), 622-629. doi:10.1002/humu.20495

Portwine, C., Lees, J., Verselis, S., Li, F. P., & Malkin, D. (2000). Absence of germline p16(INK4a) alterations in p53 wild type Li-Fraumeni syndrome families. J Med Genet, 37(8), E13.

Rana, H. Q., Gelman, R., LaDuca, H., McFarland, R., Dalton, E., Thompson, J., . . . Garber, J. E. (2018). Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing. J Natl Cancer Inst. doi:10.1093/jnci/djy001

Ruijs, M. W., Verhoef, S., Rookus, M. A., Pruntel, R., van der Hout, A. H., Hogervorst, F. B., . . . van 't Veer, L. J. (2010). TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. In J Med Genet (Vol. 47, pp. 421-428). England.

Schneider, K., Zelley, K., Nichols, K. E., & Garber, J. (2013a). Li-Fraumeni Syndrome. doi:https://www.ncbi.nlm.nih.gov/books/NBK1311/

Schneider, K., Zelley, K., Nichols, K. E., & Garber, J. (2013b). Li-Fraumeni Syndrome. In R. A. Pagon, M. P. Adam, H. H. Ardinger, S. E. Wallace, A. Amemiya, L. J. Bean, T. D. Bird, N. Ledbetter, H. C. Mefford, R. J. Smith, & K. Stephens (Eds.), GeneReviews. Seattle: University of Washington, Seattle. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/. doi:https://www.ncbi.nlm.nih.gov/books/NBK1311/

Sigal, A., & Rotter, V. (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res, 60(24), 6788-6793.

Sorrell, A. D., Espenschied, C. R., Culver, J. O., & Weitzel, J. N. (2013). TP53 Testing and LiFraumeni Syndrome: Current Status of Clinical Applications and Future Directions. Mol Diagn Ther, 17(1), 31-47. doi:10.1007/s40291-013-0020-0

Stone, J. G., Eeles, R. A., Sodha, N., Murday, V., Sheriden, E., & Houlston, R. S. (1999). Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline mutations in Bcl10. Cancer Lett, 147(1-2), 181-185.

Tinat, J., Bougeard, G., Baert-Desurmont, S., Vasseur, S., Martin, C., Bouvignies, E., . . . Frebourg, T. (2009). 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol, 27(26), e108- 109; author reply e110. doi:10.1200/jco.2009.22.7967

Varley, J. M. (2003). Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat, 21(3), 313- 320. doi:10.1002/humu.10185

Villani, A., Shore, A., Wasserman, J. D., Stephens, D., Kim, R. H., Druker, H., . . . Malkin, D. (2016). Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol, 17(9), 1295-1305. doi:10.1016/s1470-2045(16)30249-2

Villani, A., Tabori, U., Schiffman, J., Shlien, A., Beyene, J., Druker, H., . . . Malkin, D. (2011). Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol, 12(6), 559-567. doi:10.1016/s1470-2045(11)70119-x

Walsh, T., Casadei, S., Lee, M. K., Pennil, C. C., Nord, A. S., Thornton, A. M., . . . Swisher, E. M. (2011). Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A, 108(44), 18032-18037. doi:10.1073/pnas.1115052108

Wong, P., Verselis, S. J., Garber, J. E., Schneider, K., DiGianni, L., Stockwell, D. H., . . . Syngal, S. (2006). Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology, 130(1), 73-79. doi:10.1053/j.gastro.2005.10.014

Policy Implementation/Update Information

1/1/2019 BCBSNC will provide coverage for genetic testing for Li-Fraumeni syndrome when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)

Disclosures:

Medical policy is not an authorization, certification, explanation of benefits or a contract. Benefits and eligibility are determined before medical guidelines and payment guidelines are applied. Benefits are determined by the group contract and subscriber certificate that is in effect at the time services are rendered. This document is solely provided for informational purposes only and is based on research of current medical literature and review of common medical practices in the treatment and diagnosis of disease. Medical practices and knowledge are constantly changing and BCBSNC reserves the right to review and revise its medical policies periodically.

Blue Cross and Blue Shield of North Carolina does not discriminate on the basis of race, color, national origin, sex, age or disability in its health programs and activities. Learn more about our non-discrimination policy and no-cost services available to you.

Information in other languages: Español   中文   Tiếng Việt   한국어   Français   العَرَبِيَّة   Hmoob   ру́сский   Tagalog   ગુજરાતી   ភាសាខ្មែរ   Deutsch   हिन्दी   ລາວ   日本語

© 2025 Blue Cross and Blue Shield of North Carolina. ®, SM Marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield plans. All other marks and names are property of their respective owners. Blue Cross and Blue Shield of North Carolina is an independent licensee of the Blue Cross and Blue Shield Association.