MEDICAL POLICY – 12.04.512
Genetic Testing for Li-Fraumeni Syndrome
BCBCS Ref. Policy: 2.04.101
Effective Date:
Oct. 1, 2016
RELATED MEDICAL POLICIES:
Last Revised:
March 1, 2017
None
Replaces:
N/A
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POLICY CRITERIA | CODING | RELATED INFORMATION
EVIDENCE REVIEW | REFERENCES | HISTORY
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Introduction
Li-Fraumeni syndrome (LFS) is a rare disorder with an increased risk of developing some cancers,
especially for children and young adults. The cancers associated this disease include breast
cancer, a bone cancer called osteosarcoma, soft-tissue cancers known as sarcomas, brain
tumors, and leukemias. The syndrome is caused by changes to a specific gene called TP53.
Changes to the TP53 gene can be passed from parent to child. This policy discusses when
genetic testing for Li-Fraumeni syndrome is covered by the health plan.
Note:
The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The
rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for
providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can
be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a
service may be covered.
Policy Coverage Criteria
Test
Medical Necessity
Genetic testing for TP53
Genetic testing for TP53 mutations may be considered
mutations
medically necessary to confirm a diagnosis of Li-Fraumeni
syndrome (LFS) under the following conditions:
Test
Medical Necessity
1. In a patient who meets either the Classic LFS or the Chompret
clinical diagnostic criteria for Li-Fraumeni syndrome:
a. Classic LFS
An index patient with a sarcoma before 45 years of age

AND
A first-degree relative with any cancer before 45 years

of age
AND
Another first- or second-degree relative with any

cancer before 45 years of age or a sarcoma at any age
OR
b. Chompret criteria
An index patient 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 of age
AND at least 1 first- or second-degree relative with LFS
tumor (except breast cancer if the index patient has
breast cancer) before age 56 years of age or with
multiple tumors
OR
An index patient with multiple tumors (except multiple

breast tumors), 2 of which belong to LFS tumor
spectrum and first of which occurred before age 46
years of age
OR

An index patient with adrenocortical carcinoma (ACC)
or choroid plexus tumor, irrespective of family history
2. In women with early-onset breast cancer (diagnosed at 35
years of age or younger)
a. Early-onset breast cancer
i. The National Comprehensive Cancer Network (NCCN)1
recommends that in patients with breast cancer
diagnosed at 35 years of age or younger, TP53 testing
can be ordered concurrently with BRCA1/2 testing, or as a
follow-up test after negative BRCA 1/2 testing. It has
been estimated that among women with BRCA 1/2
Page | 2 of 18
Test
Medical Necessity
negative, early-onset breast cancer, approximately 5%
have a TP53 mutation.
The optimal strategy for confirming a TP53 mutation in an
index patient would be:

Sequencing of the entire TP53 coding region (exons 2-11),
which detects about 95% of TP53 mutations in patients with
LFS. If sequencing is negative, then:
o
Deletion/duplication analysis, which detects large
deletions/duplications. These types of mutations account
for less than 1 percent of mutations in individuals meeting
classic LFS criteria.
Genetic testing for a TP53 mutation may be considered
medically necessary in an at-risk relative of an index patient
with a known TP53 mutation (see “at risk” information below).
Genetic testing for a germline TP53 mutation is considered not
medically necessary for all other indications.
Guidelines for Relatives of Index Patients with a Known TP53 Mutation (aka, at-risk)
The patient’s medical records submitted for review for all conditions should document that
medical necessity criteria are met. The record should include the following:

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:
o
Proximity of relation to index case (first-, second-, or third-degree)
o
Mode of inheritance of mutation (autosomal dominant vs autosomal recessive)
o
Degree of penetrance of mutation (high, intermediate, low)
o
Results of detailed pedigree analysis
o
De novo mutation rate
If an index patient has a TP53 mutation, the risk to the index patient’s offspring of
inheriting the mutation is 50%. If an index patient has a TP53 mutation, the risk to other
relatives may depend on the genetic status of the index patient’s parents (i.e., it is not a de
novo mutation in the index patient). Most TP53 mutations are inherited from one of an
Page | 3 of 18
Guidelines for Relatives of Index Patients with a Known TP53 Mutation (aka, at-risk)
index patient’s parents. After a mutation has been identified in an index patient, the index
patient’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.
If a TP53 mutation is identified in 1 parent, the risk to the index patient’s siblings is 50%, the
risk to second-degree relatives (grandparents, aunts, uncles, nieces, nephews,
grandchildren) is 25%, and to third-degree relatives (first cousins, great-grandparents,
great-aunts, great-uncles) is 12.5% (Schneider et al, 1993).
Coding
CPT
Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence
81405
analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally
targeted cytogenomic array analysis)
Note: this test includes TP53 (tumor protein 53) (e.g., Li-Fraumeni syndrome, tumor
samples), full gene sequence or targeted sequence analysis of more than 5 exons
Unlisted molecular pathology procedure (Note: Duplication/deletion analysis for TP53
81479
would be reported with this code)
Note:
CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS
codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).
Related Information
Definition of Terms
De novo mutation: An alteration in a gene that is present for the first time (new) in one family
member as a result of a new mutation in a germ cell (egg or sperm) of one of the parents or in
the fertilized egg itself.
Page | 4 of 18
Germline mutation: Also known as hereditary mutation, a germline mutation is the presence of
an altered gene within the egg and sperm (germ cell) where the altered gene can be passed to
descendants.
Index patient or proband: An individual being studied or reported on. An index patient is
usually the first affected individual in a family who brings a genetic disorder to the attention of
the medical community.
Li-Fraumeni syndrome (LFS): This is a rare cancer predisposition syndrome associated with
germline mutations in the TP53 gene. A synonym is SBLA Syndrome (Sarcoma, Breast, Leukemia,
and Adrenal Gland).
TP53 gene: Provides instructions for making a protein called tumor protein p53 (TP53 or p53).
This protein acts as a tumor suppressor that regulates cell division by keeping cells from
growing and dividing too fast or in an uncontrolled way. By stopping cells with mutated or
damaged DNA from dividing, p53 helps prevent the development of tumors.
Definitions from the online Genetics Home Reference glossary http://ghr.nlm.nih.gov/,
accessed November 2016.
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.1 The first formal set of
criteria, the classic LFS criteria, was developed in 1988, and is the most stringent criteria used to
make a clinical diagnosis of LFS.1 Since the availability of genetic testing, National
Comprehensive Cancer Network (NCCN) guidelines have recommended that a positive genetic
test is required for a definitive diagnosis of LFS.7
Classic LFS
Classic LFS is defined by the presence of all of the following criteria:

An index patient with a sarcoma before 45 years of age and

A first-degree relative with any cancer before 45 years of age and

A first-degree or second-degree relative with any cancer before 45 years of age or a sarcoma
at any age2
Page | 5 of 18
Chompret Clinical Diagnostic Criteria
Chompret et al. developed criteria which were shown to have the highest positive predictive
value, and which, when combined with the classic LFS criteria, provide the highest sensitivity for
identifying individuals with LFS.8 The Chompret criteria were updated in 2009 to assist in
identifying families with milder phenotypes.9 The Chompret criteria will also identify individuals
with de novo TP53 mutations, whereas the classic LFS criteria require a family history.
Chompret Criteria

Proband (index patient) with tumor belonging to the 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 firstor second-degree relative with LFS tumor (except breast cancer if proband has breast
cancer) before age 56 years or with multiple tumors; OR

Proband with multiple tumors (except multiple breast tumors), 2 of which belong to the LFS
tumor spectrum and the first of which occurred before age 46 years; OR

Patient with ACC or choroid plexus tumor, irrespective of family history.
NCCN guidelines recommend TP53 analysis for individuals who meet classic LFS criteria,
Chompret criteria, or who have been diagnosed with early-onset breast cancer (age of diagnosis
35 years of age or younger).
Molecular Diagnosis
LFS is associated with germline mutations 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
mutations are known to cause LFS, and no other inherited phenotypes are associated specifically
with germline mutations involving TP53.2
LFS is a highly penetrant cancer syndrome, with the risks for cancer being ~50% by age 30 years,
and 90% by age 60 years.2 LFS is inherited in an autosomal dominant manner. De novo germline
TP53 mutations (no mutation is identified in either biologic parent) are estimated to be 7% to
20%.
Approximately 95% of mutations detected in TP53 gene are sequence variants (small intragenic
deletions/insertions and missense, nonsense, and splice site mutations). Large
Page | 6 of 18
deletion/duplications not readily detected by sequence analysis accounts for approximately 1%
of the mutations detected.2
Certain genotype-phenotype correlations have been reported in families with LFS and TP53
mutations. Genotype-phenotype correlations in LFS are predictive of the age of onset of tumor,
level of risk of developing tumor, and outcome in patients with TP53 germline mutations.1,2
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.
Evidence Review
This policy was created in 2014 with the most recent search of the MEDLINE database through
May 2, 2016. Literature that describes the analytic validity, clinical validity, and clinical utility of
genetic testing for Li-Fraumeni syndrome (LFS) TP53 mutations was sought.
Background
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the
development of several types of tumors. The syndrome was originally described in 1969 by 2
physician-scientists, Frederick P. Li and Joseph F. Fraumeni, based on a retrospective analysis of
families with aggressive soft tissue sarcomas in young siblings and their biologically related
cousins.1 The syndrome is caused by germline mutations in the TP53 gene. Testing for LFS
associated mutations may be useful in confirming the diagnosis of LFS and/or evaluating
mutation status in asymptomatic relatives of an index case.
Page | 7 of 18
The tumor types most closely associated with LFS include soft tissue sarcomas, premenopausal
breast cancer, brain tumors, and adrenal cortical carcinoma.2 These core cancers account for
approximately 70% to 80% of all LFS-related tumors. There is less agreement about the noncore
cancers, which account for the remaining 30% of malignancies in LFS and include a wide variety
of gastrointestinal tract, genitourinary tract, lung, skin, and thyroid cancers as well as leukemias
and lymphomas.2
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.4 Women with LFS are at greatly increased risk of
developing premenopausal breast cancer, with the median age of diagnosis being 33 years of
age.2 Male breast cancer has rarely been reported in LFS families.2 Many types of brain tumors
have been described in LFS, including astrocytomas, glioblastomas, medulloblastomas, and
choroid plexus carcinomas.2 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 (ACC). In
adults, in 1 series, it was estimated that 6% of individuals diagnosed with ACC after age 18 years
have a germline TP53 mutation.5
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 57%, and the risk of a
third malignancy, 38%.2 In 1 study of 322 mutations carriers from France, 43% of individuals had
multiple malignancies.3
Data from M.D. Anderson Cancer Center’s long-term clinical studies of LFS showed that the risk
of developing soft tissue sarcomas is greatest before the age of 10, 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.6
For individuals who have suspected LFS by clinical criteria or who are asymptomatic and have a
close relative with a known pathogenic TP53 mutation or women with early-onset breast cancer
who receive genetic testing for the TP53 gene, the evidence includes case series and crosssectional studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy
and validity, changes in reproductive decision making, and resource utilization. There is a lack of
evidence on analytic validity of testing, but the analytic validity is likely to be high if performed
under optimal laboratory conditions. There is scant evidence on the clinical validity of testing,
with the most being in the population of patients with adrenocortical carcinoma. For patients
with suspected LFS by clinical criteria, the clinical sensitivity ranges from 50% to 80%. No
Page | 8 of 18
evidence was identified on clinical specificity. Clinical utility is considered in the 2 following
situations:

Individuals with suspected LFS to confirm the diagnosis: For individuals with suspected LFS
by clinical criteria, a positive genetic test will confirm the diagnosis of LFS with higher
certainty than can be attained by clinical criteria alone. Confirmation of the diagnosis will
facilitate the overall workup for cancer susceptibility syndrome when multiple conditions are
considered. Also, the presence of a documented mutation may aid in decision making for
prophylactic mastectomy. The evidence is sufficient to determine qualitatively that the
technology results in a meaningful improvement in the net health outcome.

Asymptomatic individuals to determine future risk of LFS: For asymptomatic individuals who
have a close relative with a known pathogenic TP53 mutation, targeted testing can confirm
or exclude a mutation with high certainty. A positive genetic test will lead to increased
surveillance for LFS associated cancers, and a negative test will eliminate the need for
enhanced surveillance. Knowledge of mutation status may also inform reproductive decision
making in individuals considering offspring. The evidence is sufficient to determine
qualitatively that the technology results in a meaningful improvement in the net health
outcome.
Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in
excluding a mutation that is absent.
According to a large reference laboratory, analytic sensitivity and specificity for polymerase
chain reaction sequencing for LFS TP53 testing and deletions/duplications testing by multiplex
ligation-dependent probe amplification is greater than 95%.11
The order of testing to optimize yield would be:
1. Sequencing of the entire TP53 coding region (exons 2-11), which detects about 95% of TP53
mutations in patients with LFS. Examples of types of mutations detected by sequence
analysis include small deletions/duplications, and missense, nonsense and splice site
mutations; most are missense mutations
2. Deletion/duplication analysis, which detects large deletions/duplications involving the
coding region, exon 1, or promoter; these types of deletions/duplications are not readily
detectable by sequence analysis of the coding and flanking intronic regions of genomic
DNA. These types of mutations account for less than 1 percent of mutations found in
individuals with LFS.
Page | 9 of 18
Section Summary
There is a lack of published evidence on analytic validity of testing for TP53 mutations. It is
expected that analytic validity will be high when testing is performed according to optimal
laboratory standards. The website of 1 large laboratory claims analytic validity of greater than
95% but empirical, peer-reviewed data are not available.
Clinical Validity
Clinical validity is the diagnostic performance of the test [sensitivity, specificity, positive and
negative predictive values] in detecting clinical disease.
Approximately 80% of families with features of LFS will have an identifiable TP53 mutation.2
Families that have no identifiable TP53 mutation but share clinical features of LFS are more likely
to have a different hereditary cancer syndrome (e.g. hereditary breast-ovarian cancer
syndrome).2
Cohorts of individuals with adrenocortical carcinoma, which is diagnostic of LFS by the
Chompret criteria, have been published.12-14 In 1 study, 88 consecutive patients with
adrenocortical carcinoma were evaluated.14 Direct sequencing of exons 2 through 11 together
with multiplex ligation-dependent probe amplification was used to identify mutations. For the
entire population, 50% of individuals had a pathogenic mutation detected. The detection rate
varied by age, with 58% of individuals younger than 12 years of age having a mutation
compared with 25% of individuals between ages 12 and 20.
Section Summary
There is a small amount of evidence on the clinical validity of testing for TP53 mutations. In
patients who meet clinical criteria for LFS, the clinical sensitivity has been reported to range
between 50% and 80%. The largest amount of evidence is on patients with adrenocortical
carcinoma, which represents a subset of all patients with LFS. No evidence was identified on the
clinical specificity of testing.
Page | 10 of 18
Clinical Utility
Clinical utility is 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.
The clinical utility of genetic testing can be considered in the following clinical situations: 1)
individuals with suspected LFS, and 2) family members of individuals with LFS. These situations
will be discussed separately next.
Diagnostic Testing in Individuals with Suspected LFS
Direct evidence for the clinical utility of genetic testing to confirm a diagnosis of LFS is lacking.
An indirect chain of evidence can provide evidence of clinical utility if all the links in the chain of
evidence are intact.. The following series of questions represents the indirect chain of evidence
for diagnostic testing to confirm a diagnosis of LFS.
Are there some individuals for whom the diagnosis of LFS is uncertain following standard clinical
workup without genetic testing?
Yes. There are standardized diagnostic criteria based on personal, clinical, and family history.
However, there are limitations to these methods of diagnosis. A detailed family history may
not be complete or may not be available in many instances. There are different diagnostic
instruments that use different criteria, and they may be used alone or in combination with
each other. The population identified as having LFS will differ depending on how the
instruments are used. In addition, the available instruments do not have high overall
accuracy. Therefore, there may be considerable uncertainty about the diagnosis using clinical
criteria alone.
Can genetic testing make the diagnosis of LFS with certainty in patients with an uncertain clinical
diagnosis?
Yes, in some patients. A positive genetic test will confirm the diagnosis of LFS with high
certainty in individuals who meet clinical criteria. As a result, patients with a positive genetic
test will have a high certainty for the diagnosis of LFS, whereas the diagnosis by clinical
criteria alone has a high false- positive rate (up to 50%).
Does establishment of a definitive diagnosis of LFS lead to management changes?
Yes. In most cases, treatment and management will be unaffected by genetic testing,
because individuals with a negative genetic test are likely to be treated as presumed LFS.
Page | 11 of 18
However, there are some situations in which genetic testing may impact management. A
positive test will facilitate the workup for cancer susceptibility syndromes when multiple
conditions are considered. Knowledge of mutation status may also assist in decision-making
for prophylactic mastectomy by providing more definitive risk estimates.
Do the management changes result in improved health outcomes?
Yes. Outcomes are improved when a definitive diagnosis is made by avoiding the need for
further testing to determine whether a cancer susceptibility syndrome is present. Better
estimation of risk for breast cancer improves the capacity for informed decision making
regarding prophylactic mastectomy.
Testing Asymptomatic Individuals to Determine Future Risk of LFS
There is limited direct evidence on the clinical utility of genetic testing in this population. An
indirect chain of evidence can provide evidence of clinical utility if all the links in the chain of
evidence are intact. The following series of questions represents the indirect chain of evidence
for testing asymptomatic individuals to determine future risk of disease.
When there is a known pathogenic mutation in the family, is risk stratification by genetic testing
superior to risk stratification from standard workup alone?
Yes. Genetic testing of close relatives of an index case with a pathogenic mutation will
confirm or exclude the presence of the mutation with certainty. A positive test will confer
high risk for multiple malignancies, while a negative test will imply that an individual is at
average risk, in the absence of other high risk factors.
Does the presence of a pathogenic mutation indicate high risk for clinical disease (high
penetrance)?
Yes. TP53 mutations have high penetrance, indicating high risk for clinical disease when a
pathogenic mutation is present.
Is there a presymptomatic phase during which preventive strategies can be implemented?
Yes. The multiple malignancies associated with LFS have presymptomatic phases in which
early detection strategies can be implemented.
Does the presence of a pathogenic mutation lead to management changes?
Page | 12 of 18
Yes. The presence of a pathogenic mutation will lead to enhanced screening strategies for
LFS- associated malignancies. A negative genetic test will eliminate the need for enhanced
screening strategies.
Do management changes that result from genetic testing lead to improved health outcomes?
Yes. Enhanced screening for breast cancer in high-risk individuals improves outcomes, and
enhanced screening for lung cancer is also likely to improve outcomes. For the other LFSassociated core cancers, outcomes of screening interventions are not certain due to the
rarity of the conditions and lack of screening trials.
There is some direct evidence that enhanced screening protocols may improve outcomes. Villani
et al conducted a prospective, observational study of members of 8 LFS families who were
asymptomatic TP53 carriers.(15) Participants either chose to or to not undergo surveillance.
Surveillance included biochemical and imaging studies, which included ultrasounds, brain
magnetic resonance imaging (MRI) scans, and rapid total body MRI scans. The primary outcome
measure was detection of new cancers, and the secondary outcome measure was overall
survival. Of 33 mutation carriers identified, 18 underwent surveillance. The surveillance protocol
detected 10 asymptomatic tumors in 7 patients, which included premalignant or low-grade
tumors (3 low-grade gliomas, a benign thyroid tumor, 1 myelodysplastic syndrome), and small,
high-grade tumors (2 choroid plexus carcinomas, 2 adrenocortical carcinomas, 1 sarcoma). The 9
solid tumors detected were completely resected, and patients were in complete remission. After
a median follow-up of 24 months, all patients who had undergone surveillance were alive. In the
nonsurveillance group, 12 high-grade, high-stage tumors developed in 10 patients, of whom 2
were alive at the end of follow-up (p=0.04 vs survival in the surveillance group). Three-year
overall survival in the surveillance group was 100% and 21% in the nonsurveillance group
(p=0.155). This study is limited by the observational design that included self-selection into
screening protocols, likely resulting in selection bias. Further higher quality evidence is needed
to determine whether enhanced screening improves outcomes for TP53 mutations carriers.
Section Summary
Direct evidence of the clinical utility of TP53 testing is limited. One observational study reported
improved survival for screened patients. However, this study is limited by the observational
design that included self-selection into screening protocols, likely resulting in selection bias. An
indirect chain of evidence can demonstrate clinical utility of genetic testing for TP53 mutations.
For diagnosis, a positive genetic test will increase the certainty of LFS, facilitate the overall
workup for cancer susceptibility syndromes, and assist in decision making for prophylactic
mastectomy. For asymptomatic family members who have a close relative with a pathogenic
Page | 13 of 18
mutation, genetic testing can confirm or exclude the presence of a mutation, and direct future
screening interventions that are likely to improve outcomes.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in July 2016 did not identify any ongoing or unpublished trials
that would likely influence this review.
Summary of Evidence
For individuals who meet diagnostic criteria for Li-Fraumeni or women with early-onset breast
cancer who receive genetic testing for the TP53 gene, the evidence includes case series and
cross-sectional studies. Relevant outcomes are overall survival, disease-specific survival, test
accuracy and validity, changes in reproductive decision making, and resource utilization. There is
a lack of evidence on analytic validity of testing, but the analytic validity is likely to be high if
performed under optimal laboratory conditions. There is scant evidence on the clinical validity of
testing, with the most being in the population of patients with adrenocortical carcinoma. For
patients with suspected LFS by clinical criteria, the clinical sensitivity ranges from 50% to 80%.
No evidence was identified on clinical specificity. Clinical utility is considered in the 2 following
situations:

Diagnostic testing of individuals with suspected LFS. For with suspected LFS by clinical
criteria, a positive genetic test will confirm the diagnosis of LFS with higher certainty than
can be attained by clinical criteria alone. Confirmation of the diagnosis will facilitate the
overall workup for cancer susceptibility syndrome when multiple conditions are considered.
Also, the presence of a documented mutation may aid in decision making for prophylactic
mastectomy. The evidence is sufficient to determine qualitatively that the technology results
in a meaningful improvement in the net health outcome.

Testing asymptomatic individuals to determine future risk of LFS: For asymptomatic relatives
of an index patient with a pathogenic TP53 mutation, targeted testing can confirm or
exclude a mutation with high certainty. A positive genetic test will lead to increased
surveillance for LFS associated cancers, and a negative test will eliminate the need for
enhanced surveillance. Knowledge of mutation status may also inform reproductive decision
making in individuals considering offspring. The evidence is sufficient to determine
qualitatively that the technology results in a meaningful improvement in the net health
outcome.
Page | 14 of 18
Consideration of Age
The ages in this policy for which genetic testing for TP53 mutations are recommended to
confirm a diagnosis of Li-Fraumeni Syndrome are based on the following: The diagnosis of
classic clinical LFS criteria is based on a set of clinical criteria first developed in 1988 using salient
aspects of family history and tumor-related characteristics. The Chompret developed criteria
were shown to have the highest positive predictive value, and which, when combined with the
classic LFS criteria, provide the highest sensitivity for identifying individuals with LFS.7 The
Chompret criteria were updated in 2009 to assist in identifying families with milder phenotypes.8
The Chompret criteria will also identify individuals with de novo TP53 mutations, whereas the
classic LFS criteria require a family history. The National Comprehensive Cancer Network
guidelines recommend TP53 analysis for individuals who meet classic LFS criteria, Chompret
criteria, or who have been diagnosed with early-onset breast cancer (age of diagnosis 35 years
of age or younger).
Practice Guidelines and Position Statements
National Comprehensive Cancer Network Guidelines (NCCN)
National Comprehensive Cancer Network guidelines on genetic/familial high-risk assessment of
breast and ovarian (v.2.2016)16 recommend the following for LFS management:
Breast cancer risk, women:

Breast awareness starting at age 18 years.

Clinical breast exam every 6-12 months, starting at age 20-25 years or 5-10 years before the
earliest known breast cancer in the family.

Breast screening:
o
Age 20-29 years, annual breast MRI screening (preferred) or mammogram if MRI is
unavailable or individualized based on earliest age of onset in family

o
Age >30-75 years, annual mammogram, and breast MRI screening
o
Age >75 years, management considered on an individual basis
Discuss risk-reducing mastectomy and counsel regarding degree of protection and cancer
risk, and reconstruction options
Page | 15 of 18

Address psychosocial, social, and quality-of-life aspects of risk-reducing mastectomy
Other cancer risks:

Annual comprehensive physical exam with high index of suspicion for the cancers associated
with LFS

Consider colonoscopy every 2-5 years starting no later than 25 years of age

Therapeutic radiation therapy for cancer treatment should be avoided when possible

Discuss option to participate in novel screening approaches using 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
U.S. Preventive Services Task Force (USPSTF) Recommendations
No USPSTF guidelines for Li-Fraumeni syndrome testing have been identified.
Medicare National Coverage
No national coverage determination found.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory
service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the
Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be
licensed by CLIA for high-complexity testing. To date, the U.S> Food and Drug Administration
has chosen not to require any regulatory review of this test.
Page | 16 of 18
References
1.
Sorrell AD, Espenschied CR, Culver JO, et al. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of
clinical applications and future directions. Mol Diagn Ther. Feb 2013;17(1):31-47. PMID 23355100
2.
Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle
(WA)1993.
3.
Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. Jul
20 2015;33(21):2345-2352. PMID 26014290
4.
Ognjanovic S, Olivier M, Bergemann TL, et al. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database.
Cancer. Mar 1 2012;118(5):1387-1396. PMID 21837677
5.
Raymond VM, Else T, Everett JN, et al. Prevalence of germline TP53 mutations in a prospective series of unselected patients with
adrenocortical carcinoma. J Clin Endocrinol Metab. Jan 2013;98(1):E119-125. PMID 23175693
6.
Hwang SJ, Lozano G, Amos CI, et al. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.
Am J Hum Genet. Apr 2003;72(4):975-983. PMID 12610779
7.
Singh AD, Medina CA, Singh N, et al. Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications. Br J
Ophthalmol. Apr 2016;100(4):456-462. PMID 26231747
8.
Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J
Med Genet. Jan 2001;38(1):43-47. PMID 11332399
9.
Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline
mutations. J Clin Oncol. Mar 10 2009;27(8):1250-1256. PMID 19204208
10. Mai PL, Malkin D, Garber JE, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research
consortium. Cancer Genet. Oct 2012;205(10):479-487. PMID 22939227 http://ltd.aruplab.com/Tests/Pub/2009302 Accessed
February 2017.
11. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor
phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. Jun 2007;28(6):622-629. PMID 17311302
12. Wagner J, Portwine C, Rabin K, et al. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl
Cancer Inst. Nov 16 1994;86(22):1707-1710. PMID 7966399
13. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional consequence of TP53 mutations in pediatric
adrenocortical carcinoma: a children's oncology group study. J Clin Oncol. Feb 20 2015;33(6):602-609. PMID 25584008
14. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni
syndrome: a prospective observational study. Lancet Oncol. Jun 2011;12(6):559-567. PMID 21601526
15. National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment Breast and Ovarian v2.2016.
http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf Accessed February 2017.
History
Date
Comments
Page | 17 of 18
Date
Comments
07/14/14
New PR Policy, add to Genetic Testing section. Policy developed with literature review
through February 15, 2014. Medically necessary to confirm a diagnosis of Li-Fraumeni
syndrome in patients who meet clinical diagnostic criteria, in a patient who has been
diagnosed with early-onset breast cancer and in at-risk relatives of a proband with a
known TP53 mutation.
10/13/14
Interim Update. Revised the policy to replace the word “proband” with “index patient”
as terminology for the first affected family member who seeks medical attention for a
genetic disorder. No new references added. Policy statements intent is unchanged.
07/14/15
Annual Review. Definition of Terms added to the Policy Guidelines. Policy updated with
literature review through April, 2015. Reference 1 added; others renumbered. Table
listing the categories of genetic testing addressed in the policy added to the Appendix.
Policy statements unchanged.
10/01/16
Annual Review, approved September 13, 2016. Policy updated with literature review
through May 2, 2016. References 3, 7, and 12-14 added. Policy statements unchanged.
11/08/16
Minor update. Language to support consideration of age for application of this policy
added within the Rationale section. No change in policy statements.
03/01/17
Policy moved into new format; no change to policy statements. Duplicate information
removed.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The
Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and
local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review
and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit
booklet or contact a member service representative to determine coverage for a specific medical service or supply.
CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2017 Premera
All Rights Reserved.
Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to
the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer service representative to determine whether there are any benefit limitations
applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
Page | 18 of 18
Discrimination is Against the Law
Premera Blue Cross complies with applicable Federal civil rights laws and
does not discriminate on the basis of race, color, national origin, age,
disability, or sex. Premera does not exclude people or treat them differently
because of race, color, national origin, age, disability or sex.
Premera:
• Provides free aids and services to people with disabilities to communicate
effectively with us, such as:
• Qualified sign language interpreters
• Written information in other formats (large print, audio, accessible
electronic formats, other formats)
• Provides free language services to people whose primary language is not
English, such as:
• Qualified interpreters
• Information written in other languages
If you need these services, contact the Civil Rights Coordinator.
If you believe that Premera has failed to provide these services or
discriminated in another way on the basis of race, color, national origin, age,
disability, or sex, you can file a grievance with:
Civil Rights Coordinator - Complaints and Appeals
PO Box 91102, Seattle, WA 98111
Toll free 855-332-4535, Fax 425-918-5592, TTY 800-842-5357
Email [email protected]
You can file a grievance in person or by mail, fax, or email. If you need help
filing a grievance, the Civil Rights Coordinator is available to help you.
You can also file a civil rights complaint with the U.S. Department of Health
and Human Services, Office for Civil Rights, electronically through the
Office for Civil Rights Complaint Portal, available at
https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at:
U.S. Department of Health and Human Services
200 Independence Avenue SW, Room 509F, HHH Building
Washington, D.C. 20201, 1-800-368-1019, 800-537-7697 (TDD)
Complaint forms are available at
http://www.hhs.gov/ocr/office/file/index.html.
Getting Help in Other Languages
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ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ
ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ
ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ
ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ
800-722-1471 (TTY: 800-842-5357).
‫( فارسی‬Farsi):
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‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través de Premera Blue Cross. Es posible que haya fechas clave en este
aviso. Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura médica o ayuda con los costos. Usted
tiene derecho a recibir esta información y ayuda en su idioma sin costo
alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog):
Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang
paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon
tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue
Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring
mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang
panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na
walang gastos. May karapatan ka na makakuha ng ganitong impormasyon
at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471
(TTY: 800-842-5357).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).