MEDICAL POLICY 12.04.504

Genetic Testing for Hereditary Breast / Ovarian Cancer

Syndrome (BRCA1/BRCA2)

BCBSA Ref. Policy: 2.04.02

Effective Date: Jan. 1, 2018

Last Revised: July 27, 2018

Replaces: N/A

RELATED MEDICAL POLICIES:

12.04.63 Use of Common Genetic Variants (Single Nucleotide Polymorphisms) to

Predict Risk of Non-familial Breast Cancer

12.04.93 Genetic Cancer Susceptibility Panels Using Next - Generation Sequencing

Select a hyperlink below to be directed to that section.

POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING

RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

Hereditary breast and ovarian cancer (HBOC) syndrome increases the risk of specific cancers.

This syndrome is caused by mutations (changes) to the BRCA1 and BRCA2 genes. The mutations

can be passed from parent to child. These mutations increase the risk of breast cancer, ovarian

cancer and other cancers related to mutations in the BRCA genes.

This policy describes when genetic testing to look for BRCA1 and BRCA2 mutations is medically

necessary.

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

https://www.premera.com/medicalpolicies/12.04.63.pdfhttps://www.premera.com/medicalpolicies/12.04.63.pdfhttps://www.premera.com/medicalpolicies/12.04.93.pdf

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The Policy statements below are based on current guidelines from NCCN1 (see NCCN Position

Statement).

Note that for the purpose of familial assessment, first-, second-, or third-degree relatives are

blood relatives on the same side of the family (maternal or paternal).The maternal and paternal

sides of the family should be considered independently for familial patterns of cancer.

Genetic testing should be performed in a setting that has suitably trained healthcare providers

who can give appropriate pretest and posttest counseling and that has access to a Clinical

Laboratory Improvement Amendments (CLIA)-licensed laboratory that offers comprehensive

variant analysis.

Indication Medical Necessity Patients with cancer or

with personal history of

cancer (81211/81213/

81162)

Genetic testing for BRCA1 and BRCA2 mutations in cancer-

affected individuals may be considered medically necessary

under any of the following circumstances:

Individual from a family with a known BRCA1/BRCA2 variant

Personal history of epithelial ovarian or fallopian tube or

primary peritoneal cancer

Personal history of male breast cancer

Personal history of pancreatic cancer and Ashkenazi Jewish

ancestry

Personal history of breast cancer and one or more of the

following:

o 1st- 2nd- or 3rd-degree male relative with breast cancer

o Ethnicity associated with deleterious founder mutations (eg,

Ashkenazi Jewish descent) (see Recommended Testing

Strategy below)(81212)

o Diagnosed at age 45 years

o Two primary breast cancers (unilateral or bilateral) when

first breast cancer diagnosis occurred at age 50 years

o Diagnosed at age 50 years AND

One or more 1st-,2nd-, or 3rd-degree relative with

breast cancer, pancreatic cancer or prostate cancer

(Gleason 7) at any age OR

Unknown or limited family history

o Diagnosed at age 60 years with a triple negative (ER, PR,

HER2) breast cancer

o Diagnosed at any age AND 1 or more 1st-,2nd-, or 3rd-

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Indication Medical Necessity degree relative with breast cancer diagnosed at 50 years

o Diagnosed at any age AND 1 or more 1st-, 2nd-, or 3rd-

degree relative with epithelial ovarian or fallopian tube or

primary peritoneal cancer

o Diagnosed at any age AND 2 or more 1st-, 2nd-, or 3rd-

degree relative with breast cancer at any age

o Diagnosed at any age AND 2 or more first-, second-, or

third-degree relative with pancreatic cancer or prostate

cancer (Gleason 7) at any age

Personal history of pancreatic cancer or prostate cancer

(Gleason 7) at any age AND one or more 1st-, 2nd-, or 3rd-

degree relative with either:

o Breast cancer at age 50

OR

o Ovarian or fallopian tube or primary peritoneal cancer at

any age

Personal history of pancreatic cancer or prostate cancer

(Gleason 7) at any age AND 2 or more 1st-, 2nd-, or 3rd-

degree relatives with breast, pancreatic cancer or prostate

cancer (Gleason 7) at any age

Unless criteria above are met, genetic testing is considered

investigational.

Patients with family history

only (81211/81213/81162)

Genetic testing for BRCA1 and BRCA2 variants of cancer-

unaffected individuals may be considered medically necessary

under either of the following circumstances:

Individual is from a family with a known BRCA1/BRCA2 variant

OR

The affected family member is unavailable or unwilling to be

tested

AND

1st or 2nd-degree blood relative meeting any criterion listed

above for Patients with Cancer

OR

3rd-degree blood relative with breast cancer and/or ovarian or

fallopian tube or primary peritoneal cancer AND two or more

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Indication Medical Necessity 1st-, 2nd-, or 3rd-degree relatives with breast cancer (1 at age

50 years) and/or ovarian or fallopian tube or primary

peritoneal cancer

Unless criteria above are met, genetic testing is considered

investigational.

Note: Significant limitations of interpreting test results for an unaffected

individual should be discussed. Testing of unaffected individuals should only be

considered when an appropriate affected family member is unavailable for testing.

See Testing Unaffected Individuals in Related Information.

Testing of affected family

member not covered by

plan

Testing of the affected family member not covered by the Plan

may be considered medically necessary to provide the medical

information necessary for decision making for the unaffected

plan member only when all of the following criteria are met:

The information is needed to adequately assess risk in the Plan

member

AND

The information will be used in the immediate care plan of the

Plan member

AND

The non-Plan members benefit plan (if any) will not cover the

test. A copy of the denial letter from the non-Plan members

benefit plan must be provided.

Unless criteria above are met, genetic testing is considered not

medically necessary.

Documentation Requirements Provide supporting documentation for:

1. For patients with cancer or personal history of cancer and ANY of the conditions below:

o A known BRCA1/BRCA2 variant

o Personal history of epithelial ovarian or fallopian tube or primary peritoneal cancer

o Personal history of male breast cancer

o Personal history of pancreatic cancer and Ashkenazi Jewish ancestry

o Personal history of breast cancer and any family members with history of cancer of the

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Documentation Requirements breast, pancreas, prostate, ovarian, fallopian tube or primary peritoneal.

2. For patients with family history only:

o The affected family member is unavailable or unwilling to be tested

OR

o A known BRCA1/BRCA2 variant

AND

o Any conditions listed in number 1, above

3. Testing of affected family member not covered by plan when:

o The result of testing is needed to assess the risk of the member covered by the plan

AND

o The test result is to be used for immediate treatment care plan of the member

AND

o The non-Plan members benefit plan (if any) will not cover the test. A copy of the denial

letter from the non-Plan members benefit plan must be provided

Recommended Testing Strategy

Patients who meet criteria for genetic testing as outlined in the Policy statements above should

be tested for variants in BRCA1 and BRCA2.

In patients with a known familial BRCA variant, targeted testing for the specific variant is

recommended.

In patients with unknown familial BRCA variant:

o Non-Ashkenazi Jewish descent

To identify clinically significant variants, NCCN advises testing a relative who has

breast or ovarian cancer, especially with early-onset disease, bilateral disease,

multiple primaries, or ovarian cancer-because that individual has the highest

likelihood of a positive test result.

If no living family member with breast or ovarian cancer exists, NCCN suggests

testing first- or second-degree family members affected with cancer thought to be

related to deleterious BRCA1/BRCA2 variants (eg, prostate cancer, pancreatic cancer,

melanoma).

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If no familial variant can be identified, 2 possible testing strategies are:

Full sequencing followed by testing for common large genomic rearrangements

(deletions/duplications) only if sequencing detects no variant (negative result). -

More than 90% of BRCA variants will be detected by full sequencing.

Alternatively, simultaneous full sequencing and testing for common large

genomic rearrangements (also known as comprehensive BRCA testing; see

Comprehensive Variant Analysis, below) may be performed as is recommended

by NCCN.- Comprehensive testing can detect 92.5% of BRCA1/BRCA2 variants.

If comprehensive BRCA testing is negative, testing for uncommon large genomic

rearrangements (eg, BART) may be done.

Testing for uncommon large rearrangements should not be done unless both

sequencing and testing for common large rearrangements have been performed

and are negative. Among patients with negative comprehensive testing, BART

identified a deleterious variant (positive result) in less than 1%.

o Ashkenazi Jewish descent or other known Founder Mutation restricted groups (81212)

In patients of known Ashkenazi Jewish descent, the NCCN recommends testing for

the 3 known founder mutations, (185delAG and 5182insC in BRCA1; 6174delT in

BRCA2) first.

If testing is negative for founder mutations, comprehensive genetic testing may be

considered (see Comprehensive Variant Analysis, below)

Coding

Code Description

CPT 81162 BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene

analysis; full sequence analysis and full duplication/deletion analysis

81211 BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene

analysis; full sequence analysis and common duplication/deletion variants in BRCA1

81212 BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene

analysis; 185delAG, 5385insC, 6174delT variants (Founder mutations)

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Code Description

81213 BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene

analysis; uncommon duplication/deletion variants [BART]

81214 BRCA1 (breast cancer 1) (eg, hereditary breast and ovarian cancer) gene analysis; full

sequence analysis and common duplication/deletion variants (ie, exon 13 del 3.835kb,

exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb)

81215 BRCA1 (breast cancer 1) (eg, hereditary breast and ovarian cancer) gene analysis;

known familial variant

81216 BRCA2 (breast cancer 2) (eg, hereditary breast and ovarian cancer) gene analysis; full

sequence analysis

81217 BRCA2 (breast cancer 2) (eg, hereditary breast and ovarian cancer) gene analysis;

known familial variant

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

First-, second-, or third- degree relative: For the purpose of familial assessment, first-,

second-, or third-degree relatives are blood relatives on the same side of the family (maternal or

paternal). The maternal and paternal sides of the family should be considered independently for

familial patterns of cancer.

First-degree relatives are parents, siblings, and children.

Second-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren,

and half-siblings.

Third-degree relatives are great-grandparents, great-aunts, great-uncles, great-

grandchildren, and first cousins.

Unknown or limited family history: Limited family history represents fewer than two first- or

second-degree female relatives having lived beyond age 45 in either lineage. In families with a

large number of unaffected female relatives, the likelihood of variant detection may be very low.

Unknown family history is typically because of adoption.

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Consideration of Age

The ages described in the policy statements are based on current guidelines from the National

Comprehensive Cancer Network.

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 individuals 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

Description

Hereditary breast and ovarian cancer syndrome describes the familial cancer syndromes related

to variants in the BRCA genes (BRCA1 located on chromosome 17q21, BRCA2 located on

chromosome 13q12-13). Families with hereditary breast and ovarian cancer syndrome have an

increased susceptibility to the following types of cancer: breast cancer occurring at a young age,

bilateral breast cancer, male breast cancer, ovarian cancer (at any age), cancer of the fallopian

tube, primary peritoneal cancer, prostate cancer, pancreatic cancer, gastrointestinal cancers,

melanoma, and laryngeal cancer.

Background

Several genetic syndromes with an autosomal dominant pattern of inheritance that feature

breast cancer have been identified. Of these, HBOC and some cases of hereditary site-specific

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breast cancer have in common causative mutations in BRCA (breast cancer susceptibility) genes.

Families suspected of having HBOC syndrome are characterized by an increased susceptibility to

breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian

cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other

cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and

laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer

families are characterized by early onset breast cancer with or without male cases, but without

ovarian cancer. For this policy, both will be referred to collectively as hereditary breast and/or

ovarian cancer.

Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in

most HBOC families, especially if ovarian cancer or male breast cancer are features. However, in

site-specific breast cancer, BRCA mutations are responsible only for a proportion of affected

families. BRCA gene variants are inherited in an autosomal dominant fashion through either the

maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes

to identify the specific variant in cancer cases and to identify family members with increased

cancer risk. Family members without existing cancer who are found to have BRCA variants can

consider preventive interventions for reducing risk and mortality.

Comprehensive Variant Analysis

Comprehensive variant analysis currently includes sequencing the coding regions and

intron/exon splice sites, as well as tests to detect common large deletions and rearrangements

that can be missed with sequence analysis alone. In addition, before August 2006, testing for

large deletions and rearrangements such as BART was not performed, thus some patients with

familial breast cancer who had negative BRCA testing before this time may consider repeat

testing for the rearrangements (see Policy Coverage for criteria).

High-Risk Ethnic Groups

Testing of eligible individuals who belong to ethnic populations in which there are well-

characterized founder mutations should begin with tests specifically for these variants. For

example, founder mutations account for approximately three-quarters of the BRCA variants

found in Ashkenazi Jewish populations. When testing for founder mutations is negative,

comprehensive variant analysis should then be performed.

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Note: Founder mutations are associated with certain ethnic backgrounds and are not necessarily tied to specific

countries. Requests for founder mutation testing other than Ashkenazi Jewish heritage will be considered on

a case-by-case basis.

Testing Unaffected Individuals

In unaffected family members of potential BRCA mutation families, most test results will be

negative and uninformative. Therefore, it is strongly recommended that an affected family

member be tested first whenever possible to adequately interpret the test. Should a BRCA

mutation be found in an affected family member(s), DNA from an unaffected family member can

be tested specifically for the same mutation of the affected family member without having to

sequence the entire gene. Interpreting test results for an unaffected family member without

knowing the genetic status of the family may be possible in the case of a positive result for an

established disease-associated mutation but leads to difficulties in interpreting negative test

results (uninformative negative) or mutations of uncertain significance because the possibility of

a causative BRCA mutation is not ruled out.

Prostate Cancer

Patients with BRCA variants have an increased risk of prostate cancer, and patients with known

BRCA variants may therefore consider more aggressive screening approaches for prostate

cancer. However, the presence of prostate cancer in an individual, or in a family, is not itself

considered sufficient justification for BRCA testing.

Summary of Evidence

For individuals who have cancer or a personal or family cancer history and meet criteria

suggesting a risk of hereditary breast and ovarian cancer syndrome who receive genetic testing

for a BRCA1 or BRCA2 variant, the evidence includes a TEC Assessment and studies of variant

prevalence and cancer risk. Relevant outcomes are overall survival, disease-specific survival, test

accuracy and validity, and quality of life. The accuracy of the test has been shown to be high.

Studies of lifetime risk of cancer for carriers of a BRCA mutation have shown a risk as high as

85%. Knowledge of variant status in individuals at risk of a BRCA mutation may impact health

care decisions to reduce risk, including intensive surveillance, chemoprevention, and/or

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prophylactic intervention. The evidence is sufficient to determine qualitatively that the

technology results in a meaningful improvement in the net health outcome.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Active Trials of BRCA Mutation Testing

NCT Number Title Enrollment a Completion Date b

NCT02225015 Cancer Prevention in Women With a BRCA

Mutation

300 Jun 2019

NCT02321228 Early Salpingectomy (Tubectomy) With

Delayed Oophorectomy in BRCA1/2 Gene

Mutation Carriers (TUBA)

510 Jan 2035

NCT02154672 Prostate Cancer Screening in Men With

Germline BRCA2 Mutations

100 May 2018

aExpected

bEstimated

Clinical Input Received From Physician Specialty Societies and Academic

Medical Centers

While the various physician specialty societies and academic medical centers may collaborate

with and make recommendations during this process, through the provision of appropriate

reviewers, input received does not represent an endorsement or position statement by the

physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 3 physician specialty societies (5 reviewers)

and 3 academic medical centers (5 reviewers) while this policy was under review for January

2010. Those providing input were in general agreement with the Policy statements considering

testing for genomic rearrangements of BRCA1 and BRCA2 as medically necessary and with

adding fallopian tube and primary peritoneal cancer as additional BRCA-associated malignancies

to assess when obtaining the family history.

https://www.clinicaltrials.gov/ct2/show/NCT02225015?term=NCT02225015&rank=1https://www.clinicaltrials.gov/ct2/show/NCT02321228?term=NCT02321228&rank=1https://www.clinicaltrials.gov/ct2/show/NCT02154672?term=NCT02154672&rank=1

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Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The current National Comprehensive Cancer Network (NCCN) guidelines on genetic and familial

high-risk assessment of breast and ovarian cancers (version 2.2018) include criteria for

identifying individuals who should be referred for further risk assessment, and separate criteria

for genetic testing50. Patients who satisfy any of the testing criteria listed in Table 2 should

undergo further personalized risk assessment, genetic counseling, and often genetic testing

and management. For these criteria, both invasive and in situ breast cancers are included.

Maternal and paternal sides of the family should be considered independently for familial

patterns of cancer. Testing of unaffected individuals should be considered only when an

appropriate affected family member is unavailable for testing.

BRCA1 and BRCA2 somatic variants are not common. The National Comprehensive Cancer

Network recommends if a somatic variant is identified through tumor profiling, then BRCA1 and

BRCA2 germline testing is recommended.

Table 2. BRCA1 and BRCA2 Testing Criteria for Hereditary Breast and

Ovarian Cancer Syndrome

Recommendations

1. Individual from a family with a known BRCA1/BRCA2 mutation

2. Personal history of breast cancer and 1 of the following:

a. Diagnosed age 45 years

b. Diagnosed age 50 years AND:

i. An additional breast cancer primary

ii. 1 close blood relative with breast cancer at any age

iii. 1 close relative with pancreatic cancer

iv. 1 close relative with prostate cancer (Gleason score 7), or

v. Unknown or limited family history

c. Diagnosed age 60 years with a triple-negative (ER, PR, HER2) breast cancer

d. Diagnosed any age AND

i. 2 close blood relatives with breast, pancreatic or prostate cancer (Gleason score 7) at any

age

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Recommendations

ii. 1 close blood relative with breast cancer diagnosed at age 50 or younger

iii. 1 close blood relative with ovarian cancer or

iv. A close male blood relative with breast cancer

v. For an individual of ethnicity associated with higher mutation frequency (eg Ashkenazi Jewish),

no additional family history may be required

3. Personal history of ovarian cancer

4. Personal history of male breast cancer

5. Personal history of prostate cancer (Gleason score 7) at any age AND 1 close blood relative with ovarian

cancer at cancer at any age or breast cancer at or before age 50 or 2 relatives with breast, pancreatic or

prostate cancer (Gleason score 7) at any age.

6. Personal history of pancreatic cancer at any age AND 1 blood relative with ovarian cancer at any age or

breast cancer at or before age 50 or 2 relatives with breast, pancreatic or prostate cancer (Gleason score 7

or metastatic) at any age For an individual of ethnicity associated with higher mutation frequency (eg

Ashkenazi Jewish), no additional family history may be required

7. BRCA1/2 mutation detected by tumor profiling in the absence of germline mutation analysis

8. Family history only

a. 1st- or 2nd-degree blood relative meeting any of the above criteria

b. 3rd-degree blood relative with breast cancer and/or ovarian/fallopian tube/primary peritoneal cancer

AND 2 1st-, 2nd-, or 3rd-degree relatives with breast cancer (1 at age 50 years) and/or ovarian

cancer

ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; PR: progesterone receptor.

American Society of Clinical Oncology

The American Society of Clinical Oncology recommended in 2003 that cancer predisposition

testing be offered when three factors are at play: (1) there is a personal or family history

suggesting genetic cancer susceptibility, (2) the test can be adequately interpreted, and (3)

results will influence medical management of the patient or family member at hereditary risk of

cancer51. A 2010 update of this statement recommended that genetic tests with uncertain

clinical utility, including genomic risk assessment, be administered in the context of clinical

trials.52

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Society of Gynecologic Oncology

In 2014, Society of Gynecologic Oncology (SGO) published an evidence-based consensus

statement on risk assessment for inherited gynecologic cancer.53 The statement includes criteria

for recommending genetic assessment (counseling with or without testing) to patients who may

be genetically predisposed to breast or ovarian cancer. Overall, SGO and NCCN

recommendations are very similar; the main differences being the exclusion of women with

breast cancer onset at age 50 years or younger who have one or more first-, second-, or third-

degree relatives with breast cancer at any age; women with breast cancer or history of breast

cancer who have a first-, second-, or third-degree male relative with breast cancer; and men with

a personal history of breast cancer. Additionally, SGO recommended genetic assessment for

unaffected women who have a male relative with breast cancer. Moreover, SGO indicated that

some patients who do not satisfy criteria may still benefit from genetic assessment (eg, few

female relatives, hysterectomy or oophorectomy at a young age in multiple family members, or

adoption in the lineage).

U.S. Preventive Services Task Force (USPSTF) Recommendations

Current U.S. Preventive Services Task Force (USPSTF) recommendations for genetic testing of

BRCA1 and BRCA2 variants in women are listed next.54

Population Women who have family members with breast, ovarian,

tubal, or peritoneal cancer

The USPSTF recommends that primary care providers screen women who have family members

with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to

identify a family history that may be associated with an increased risk for potentially harmful

mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive

screening results should receive genetic counseling and, if indicated after counseling, BRCA

testing. (Grade B Recommendation).

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Population Women whose family history is not associated with an

increased risk

The USPSTF recommends against routine genetic counseling or BRCA testing for women whose

family history is not associated with an increased risk for potentially harmful mutations in the

BRCA1 or BRCA2 genes (Grade D recommendation).

Screening Tools

Recommended screening tools designed to identify a family history that may be associated

with an increased risk for potentially harmful variants in BRCA1 or BRCA2 are:

Ontario Family History Assessment Tool (FHAT)

Manchester Scoring System

Referral Screening Tool (RST)

Pedigree Assessment Tool (PAT)

Family History Screen (FHS-7)

Medicare National Coverage

There are no national coverage determinations. There is a local coverage determination by

Palmetto MolDx Program, which determined that BRCA1- and BRCA2-targeted mutation

analysis (familial or founder mutation), sequencing with common deletion and duplication

analysis, and uncommon deletion and duplication analysis meets Medicare criteria for a covered

service.55

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 Act (CLIA). Per the genetests.org website, there are currently 6

CLIA-certified U.S. laboratories that offer sequence analysis of the entire coding and 4 that offer

deletion/duplication/copy number analysis. Laboratories that offer LDTs must be licensed by

http://www.genetests.org/

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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.

Myriad Genetic Laboratories (Salt Lake City, UT) offers (1) Comprehensive BRACAnalysis that

includes complete sequencing of BRCA1/BRCA2 and gap polymerase chain reaction for 5

common rearrangements (deletions/duplications) in BRCA1; (2) BRACAnalysis Large

Rearrangement Test (BART), which may be ordered as a reflex for patients who test negative

for Comprehensive BRACAnalysis to detect uncommon large rearrangements in BRCA1 and

BRCA2; (3) the Integrated BRACAnalysis, which includes BART as part of BRCA1/BRCA2

analysis, and (4) the BRACAnalysi CDxs, which is intended to detect germline BRCA1 and

BRCA2 variants to aid in identifying ovarian cancer patients who may be considered for

treatment with olaparib.

Quest Diagnostics (Madison, NJ) offers BRCAvantage that includes sequencing of

BRCA1/BRCA2 and a multiplex ligation-dependent probe amplification assay to detect both

common and uncommon gene rearrangements.

LabCorp (Burlington, NC) offers the BRCAssureSM suite of tests, which includes: targeted

BRCA1/BRCA2 analysis; a founder mutation panel for Ashkenazi Jewish patients (3 variants);

comprehensive BRCA1/BRCA2 analysis (full gene sequencing plus analysis of common and

uncommon large rearrangements); and deletion/duplication analysis of uncommon large

rearrangements only (without sequencing) when comprehensive analysis is negative.

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PMID 9544766

17. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast

cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. Mar 1998;62(3):676-689. PMID 9497246

18. Gershoni-Baruch R, Patael Y, Dagan, et al. Association of the I1307K APC mutation with hereditary and sporadic breast/ovarian

cancer: more questions than answers. Br J Cancer. Jul 2000;83(2):153-155. PMID 10901363

19. Hartge P, Struewing JP, Wacholder S, et al. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews.

Am J Hum Genet. Apr 1999;64(4):963-970. PMID 10090881

20. Hodgson SV, Heap E, Cameron J, et al. Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi

Jewish women with breast or ovarian cancer. J Med Genet. May 1999;36(5):369-373. PMID 10353781

21. de Ruijter TC, Veeck J, de Hoon JP, et al. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol. Feb

2011;137(2):183-192. PMID 21069385

22. Kandel MJ, Stadler D, Masciari S, et al. Prevalence of BRCA1 mutations in triple negative breast cancer (BC) [abstract 508]. J Clin

Oncol. 2006;24(18S):508.

23. Young SR, Pilarski RT, Donenberg T, et al. The prevalence of BRCA1 mutations among young women with triple-negative breast

cancer. BMC Cancer. Mar 19 2009;9:86. PMID 19298662

24. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple

receptor-negative breast cancer. Clin Cancer Res. Mar 1 2011;17(5):1082-1089. PMID 21233401

25. Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg. Oct 2010;44:293-311. PMID 20919528

26. Couch FJ, Johnson MR, Rabe KG, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol

Biomarkers Prev. Feb 2007;16(2):342-346. PMID 17301269

27. Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin

Oncol. Jan 20 2009;27(3):433-438. PMID 19064968

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28. Trainer AH, Meiser B, Watts K, et al. Moving toward personalized medicine: treatment-focused genetic testing of women newly

diagnosed with ovarian cancer. Int J Gynecol Cancer. Jul 2010;20(5):704-716. PMID 20973257

29. Zhang S, Royer R, Li S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian

cancer. Gynecol Oncol. May 1 2011;121(2):353-357. PMID 21324516

30. Hirst JE, Gard GB, McIllroy K, et al. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-

oophorectomy. Int J Gynecol Cancer. Jul 2009;19(5):826-829. PMID 19574767

31. Powell CB, Swisher EM, Cass I, et al. Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia

identified at risk reducing salpingo-oophorectomy. Gynecol Oncol. May 2013;129(2):364-371. PMID 23391663

32. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast

cancer. JAMA. Mar 22 2006;295(12):1379-1388. PMID 16551709

33. Palma MD, Domchek SM, Stopfer J, et al. The relative contribution of point mutations and genomic rearrangements in BRCA1

and BRCA2 in high-risk breast cancer families. Cancer Res. Sep 1 2008;68(17):7006-7014. PMID 18703817

34. Grann VR, Whang W, Jacobson JS, et al. Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2. J Clin

Oncol. Feb 1999;17(2):494-500. PMID 10080590

35. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast

cancer. N Engl J Med. Jan 14 1999;340(2):77-84. PMID 9887158

36. Menkiszak J, Rzepka-Gorska I, Gorski B, et al. Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in

Poland. Eur J Gynaecol Oncol. Apr 2004;25(1):93-95. PMID 15053071

37. Moller P, Borg A, Evans DG, et al. Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by

tumour characteristics, BRCA mutations and oophorectomy. Int J Cancer. Oct 20 2002;101(6):555-559. PMID 12237897

38. Olopade OI, Artioli G. Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations. Breast J.

Jan-Feb 2004;10 Suppl 1:S5-9. PMID 14984481

39. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med.

May 23 2002;346(21):1616-1622. PMID 12023993

40. Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA

mutation carriers. J Clin Oncol. Mar 1 2002;20(5):1260-1268. PMID 11870168

41. Weitzel JN, McCaffrey SM, Nedelcu R, et al. Effect of genetic cancer risk assessment on surgical decisions at breast cancer

diagnosis. Arch Surg. Dec 2003;138(12):1323-1328; discussion 1329. PMID 14662532

42. Finch AP, Lubinski J, Moller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or

BRCA2 mutation. J Clin Oncol. May 20 2014;32(15):1547-1553. PMID 24567435

43. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer

risk and mortality. Jama. Sep 01 2010;304(9):967-975. PMID 20810374

44. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta-analysis and

systematic review. Clin Cancer Res. Aug 1 2016;22(15):3971-3981. PMID 26979395

45. Ludwig KK, Neuner J, Butler A, et al. Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a

systematic review. Am J Surg. Jul 18 2016. PMID 27649974

46. Marchetti C, De Felice F, Palaia I, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk

and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. Dec 12 2014;14:150. PMID 25494812

47. Phillips KA, Jenkins MA, Lindeman GJ, et al. Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and

BRCA2 mutation carriers: a prospective cohort study. Clin Genet. Sep 2006;70(3):198-206. PMID 16922722

48. Nelson HD, Pappas M, Zakher B, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in

women: a systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med. Feb 18

2014;160(4):255-266. PMID 24366442

Page | 19 of 23

49. Mitra AV, Bancroft EK, Barbachano Y, et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2

detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. Jan 2011;107(1):28-39. PMID

20840664

50. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High Risk

Assessment: Breast and Ovarian. Version 1.20180.

https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf Accessed December 2017.

51. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for

cancer susceptibility. J Clin Oncol. Jun 15 2003;21(12):2397-2406. PMID 12692171

52. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic

testing for cancer susceptibility. J Clin Oncol. Feb 10 2010;28(5):893-901. PMID 20065170

53. Lancaster JM, Powell CB, Chen LM, et al. Society of Gynecologic Oncology statement on risk assessment for inherited

gynecologic cancer predispositions. Gynecol Oncol. Jan 2015;136(1):3-7. PMID 25238946

54. Moyer VA. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services

Task Force recommendation statement. Ann Intern Med. Feb 18 2014;160(4):271-281. PMID 24366376

55. Center for Medicare & Medicaid Services. Local Coverage Determination (LCD): MolDX: BRCA1 and BRCA2 Genetic Testing

(L36082). https://www.cms.gov/medicare-coverage-database/details/lcd-

details.aspx?LCDId=36082&ver=26&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=B

RCA&KeyWordLookUp=Title&KeyWordSearchType=And&list_type=ncd&bc=gAAAACAAAAAAAA%3d%3d& Accessed

December 2017.

History

Date Comments 03/03/98 New BC Policy BC.2.04.02Add to Medicine Section New Policyreplaces

PR.2.04.504

01/07/99 Coding Update 1999 CPT Coding Release

03/11/03 Replace Policy Revision of existing policy; candidates for genetic testing expanded to

include those with early onset breast cancer and members of high-risk populations

without an affected family member.

05/11/04 Replace Policy Policy reviewed; no change to policy statement; new HCPC codes

added.

02/08/05 New PR Policy PR.2.04.504Replace Policy Replace Policy-instituted. Replaces

BC.2.04.02

02/14/06 Replace Policy Policy reviewed with literature search; no change to policy statement.

02/22/06 Codes updated No other changes, effective date unchanged.

06/30/06 Update Scope and Disclaimer No other changes.

01/04/07 Replace Policy Policy updated with literature review; reference added. No change in

policy statement.

https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdfhttps://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36082&ver=26&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=BRCA&KeyWordLookUp=Title&KeyWordSearchType=And&list_type=ncd&bc=gAAAACAAAAAAAA%3d%3d&https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36082&ver=26&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=BRCA&KeyWordLookUp=Title&KeyWordSearchType=And&list_type=ncd&bc=gAAAACAAAAAAAA%3d%3d&https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36082&ver=26&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=BRCA&KeyWordLookUp=Title&KeyWordSearchType=And&list_type=ncd&bc=gAAAACAAAAAAAA%3d%3d&

Page | 20 of 23

Date Comments 02/13/07 Replace Policy Policy updated with literature review; references added. No change in

policy statement.

03/13/07 Replace Policy Explanation of BART test, as subset of BRCA, added to Policy

Guidelines.

03/21/07 Codes Updated No other changes.

05/08/07 Replace Policy Policy statement clarified with substitution of ACMG criteria.

07/10/07 Cross Reference Update No other changes.

06/10/08 Replace Policy Policy updated with literature search. Policy statement modified to

reflect USPTF guidelines: High risk age changed from

Page | 21 of 23

Date Comments 09/10/12 Update Coding Section ICD-10 codes are now effective 10/01/2014.

10/15/12 Replace Policy. Two bullets in No personal history section of policy statement re-

worded to clarify intent. No functional change to the policy statement.

01/14/13 Coding update. CPT codes 83890 83913 deleted as of 12/31/12; CPT codes 81200

81479 and 81599, effective 1/1/13, are added to the policy.

05/14/13 Update Related Policies. Add 12.04.91.

06/10/13 Interim update. Benefit Application section updated with federal preventative care

mandate language which covers genetic counseling and evaluation for BRCA testing

within the outlined patient population. No change in policy statements.

08/12/13 Replace policy. One first degree relative with bilateral breast cancer added to

Personal History section for clarification of policy statement. Clarification added to

Guidelines that the presence of prostate cancer alone does not justify BRCA testing.

Prostate cancer studies added to Rationale. NCCN v4.2013 revisions to criteria for

mutation testing and CHEK2 testing added to Rationale.

01/13/14 Replace policy. Policy statement revised to allow testing for unaffected individuals not

meeting criteria in Personal History or No Personal History section when additional

criteria are met. In limited circumstances, a non-Plan affected family member may

qualify for BRCA testing. Notation added to indicate that NCCN guidelines are

provided for informational purposes only and are not meant to replace the criteria in

the policy statement. Definition of close blood relative added. Title changed,

removing BRCA1 and BRCA2 Mutations to Hereditary Breast and/or Ovarian

Cancer. USPSTF 2013 Recommendations added to Rationale. Deleted CPT codes

83890 83912 removed; 81479 and 81599 removed (they refer to a different policy);

modifiers 0A and 0B removed, along with ICD-9 procedure code 99.99 (this policy is

not auto adjudicated); and deleted HCPCS codes S3818 - S3823 removed from policy.

06/27/14 Update Related Policies. Remove 12.04.57 as it was deleted.

07/24/14 Update Related Policies. Remove 12.04.91.

05/12/15 Annual review. Policy statement extensively revised based on guidelines from NCCN.

Information on BART retained and CHEK2 deleted. Reference to early age deleted

and replaced by criteria-specific ages. Clarification added regarding family lineage and

founder mutations. Qualifying criteria added regarding prostate cancer. Rationale and

References revised.

06/16/15 Clarification only. Policy section reformatted to provide improved clarity; no change in

content, additions or deletions.

08/27/15 Update Related Policies. Add 12.04.516 and 7.01.09.

02/09/16 Annual Review. Policy updated with literature review through October 7, 2015; no

references added. Policy statement regarding BART clarified; documentation must be

submitted indicating that patient met criteria for BRCA testing and that standard BRCA

sequence analysis was negative. Unless those criteria are met, BART is considered not

Page | 22 of 23

Date Comments medically necessary. Coding update New CPT code 81162, effective 1/1/16, added to

policy.

05/04/16 Update related policies. Policy 7.01.09 was deleted and replaced with policy 7.01.561.

11/01/16 Interim Update, approved October 11, 2016. Policy statement regarding pancreatic

and prostate cancer revised to reflect current NCCN guidelines. Clarification of the

definitions of unknown or limited family history. Policy moved into new format:

removed repeated content and reordered some content in Related Information and

Evidence sections.

01/01/17 Interim review, approved December 13, 2016. Language added to Evidence Review

section to indicate the ages described in the policy statements are based on current

guidelines from the NCCN. Policy statement revised: Moved clarification note

regarding familial assessment to top of Policy Coverage criteria and added language

of medical necessity for BART when comprehensive testing is negative or VUS

detected. Testing of 3 variants of common founder mutations (CPT 81212) clarified: It

is recommended, although not required, that those with a personal history of breast

cancer and of Ashkenazi Jewish descent be tested for the common founder mutations

before proceeding to comprehensive testing.

03/01/17 Updated Related Policies, removed 12.04.516 as it was deleted (contents moved to

12.04.126).

03/07/17 Minor formatting update.

06/01/17 Minor edit, reformatted bullets in the Policy Criteria section for clarity.

11/01/17 Updated Related Policies, removed 7.01.561 as it was archived.

01/01/18 Annual Review, approved December 6, 2017. Policy updated with literature review

through September 2017; references updated. Policy statement reformatted to provide

improved clarity; policy intent unchanged. Statement regarding BART testing removed;

as it can be allowed if BRCA 1/BRCA2 criteria are met.

03/09/18 Minor update; added Documentation Requirements section.

05/25/18 Minor edit, reordered bullets in the Policy Criteria section for clarity.

07/27/18 Coding update, removed CPT 96040.

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.

Page | 23 of 23

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). 2018 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.

037338 (07-2016)

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Romn (Romanian): Prezenta notificare conine informaii importante. Aceast notificare poate conine informaii importante privind cererea sau acoperirea asigurrii dumneavoastre de sntate prin Premera Blue Cross. Pot exista date cheie n aceast notificare. Este posibil s fie nevoie s acionai pn la anumite termene limit pentru a v menine acoperirea asigurrii de sntate sau asistena privitoare la costuri. Avei dreptul de a obine gratuit aceste informaii i ajutor n limba dumneavoastr. Sunai la 800-722-1471 (TTY: 800-842-5357). P (Russian): . Premera Blue Cross. . , , . . 800-722-1471 (TTY: 800-842-5357). Faasamoa (Samoan): Atonu ua iai i lenei faasilasilaga ni faamatalaga e sili ona taua e tatau ona e malamalama i ai. O lenei faasilasilaga o se fesoasoani e faamatala atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua atu i ai. Faamolemole, ia e iloilo faalelei i aso faapitoa oloo iai i lenei faasilasilaga taua. Masalo o lea iai ni feau e tatau ona e faia ao lei aulia le aso ua taua i lenei faasilasilaga ina ia e iai pea ma maua fesoasoani mai ai i le polokalame a le Malo oloo e iai i ai. Oloo iai iate oe le aia tatau e maua atu i lenei faasilasilaga ma lenei famatalaga i legagana e te malamalama i ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471 (TTY: 800-842-5357). Espaol (Spanish): Este Aviso contiene informacin importante. Es posible que este aviso contenga informacin importante acerca de su solicitud o cobertura a travs 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 mdica o ayuda con los costos. Usted tiene derecho a recibir esta informacin 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). (Thai): Premera Blue Cross 800-722-1471 (TTY: 800-842-5357) (Ukrainian): . Premera Blue Cross. , . , , . . 800-722-1471 (TTY: 800-842-5357). Ting Vit (Vietnamese): Thng bo ny cung cp thng tin quan trng. Thng bo ny c thng tin quan trng v n xin tham gia hoc hp ng bo him ca qu v qua chng trnh Premera Blue Cross. Xin xem ngy quan trng trong thng bo ny. Qu v c th phi thc hin theo thng bo ng trong thi hn duy tr bo him sc khe hoc c tr gip thm v chi ph. Qu v c quyn c bit thng tin ny v c tr gip bng ngn ng ca mnh min ph. Xin gi s 800-722-1471 (TTY: 800-842-5357).