Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)

POLICY NUMBER

A.2.04.02

DESCRIPTION

Hereditary breast and ovarian cancer syndrome describe the familial cancer syndromes related to variants in the BRCA genes (BRCA1 located on chromosome 17q21, BRCA2 located on chromosome 13q12-13). The PALB2 gene is located at 16p12.2 and has 13 exons. PALB2 protein assists BRCA2 in DNA repair and tumor suppression. 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.

Hereditary Breast and Ovarian Cancer Syndrome

Several genetic syndromes with an autosomal dominant pattern of inheritance that features breast cancer have been identified. Of these, hereditary breast and ovarian cancer (HBOC) syndrome and some cases of hereditary site-specific breast cancer have in common causative variants 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 cancer, BRCA variants are responsible for only a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through 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.

Evidence suggests that genetic services are not equitably applied. Chapman-Davis and colleagues found that non-Hispanic Whites and Asians were more likely to be referred for genetic services based solely on family history than were non-Hispanic Blacks and Hispanics. In addition, non-Hispanic Black patients and Hispanic patients were more likely to have advanced cancer when referred for genetic services than non-Hispanic Whites and Asians.

Clinical Features Suggestive of BRCA Variant

Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. A 1996 study estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30 years. In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35 to 50 years). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s. In the Ashkenazi Jewish population, it was reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants. In a similar study, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants. Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population.

As in the general population, a family history of breast or ovarian cancer, particularly of early age onset, is a significant risk factor for a BRCA variant in ethnic populations characterized by founder mutations. For example, in unaffected individuals of Ashkenazi Jewish descent, 12% to 31% will have a BRCA variant depending on the extent and nature of the family history. Several other studies have documented the significant influence of family history.

In patients with “triple-negative” breast cancer (ie, negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for the development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer. In 200 randomly selected patients with triple-negative breast cancer from a tertiary care center, it was reported there was a greater than 3-fold increase in the expected rate of BRCA variants. BRCA1 variants were found in 39.1% of patients and BRCA2 variants in 8.7%. A study of 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing. Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, in a study of 77 patients with triple-negative breast cancer, it was reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2).

PALB2 Gene

The PALB2 gene (partner and localizer of BRCA2) encodes for a protein first described in 2006. The gene is located at 16p12.2 [Short (p) arm of chromosome 16 at position 12.2.] and has 13 exons. PALB2 protein assists BRCA2 in DNA repair and tumor suppression. Heterozygous pathogenic PALB2 variants increase the risk of developing breast and pancreatic cancers; homozygous variants are found in Fanconi anemia. Fanconi anemia is a rare disorder, primarily affecting children, that causes bone marrow failure. Affected individuals also carry a risk of cancers including leukemia. Most pathogenic PALB2 variants are truncating frameshift or stop codons, and are found throughout the gene. Pathogenic PALB2 variants are uncommon in unselected populations and prevalence varies by ethnicity and family history. For example, one study assumed a prevalence of 8 per 10,000 in the general population when modeling breast cancer risks. Variants are more prevalent in ethnic populations where founder mutations have persisted (eg, Finns, French Canadians, Poles), while infrequently found in others (eg, Ashkenazi Jews). In women with a family history of breast cancer, the prevalence of pathogenic PALB2 variants ranges between 0.9% and 3.9%, or substantially higher than in an unselected general population. Depending on population prevalence, PALB2 may be responsible for as much as 2.4% of hereditary breast cancers; and in populations with founder mutations cause 0.5% to 1% of all breast cancers.

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

POLICY

Genetic testing should be performed in a setting that has suitably trained health care providers who can give appropriate pre- and post-test counseling and that has access to a Clinical Laboratory Improvement Amendments-licensed laboratory that offers comprehensive variant analysis (see Policy Guidelines section: Comprehensive Variant Analysis).

Individuals With Cancer or With a Personal History of Cancer

Genetic testing for BRCA1,BRCA2, and PALB2 variants in cancer-affected individuals may be considered medically necessary under any of the following circumstances:

• Individuals with any close blood relative with a known BRCA1, BRCA2, or PALB2 pathogenic/likely pathogenic variant (see Policy Guidelines for definitions and for testing strategy).

• Individuals meeting the criteria below but with previous limited testing (eg, single gene and/or absent deletion duplication analysis)

• Personal history of breast cancer and one or more of the following:

  • Diagnosed at age ≤45 years; or

  • Diagnosed at age 46 to 50 years with:

    • An additional breast cancer primary at any age; or

    • ≥1 close relative (see Policy Guidelines) with breast, ovarian, pancreatic, or prostate cancer at any age; or

    • An unknown or limited family history

  • Diagnosed ≤60 years with:

    • Triple-negative breast cancer (see Policy Guidelines)

  • Diagnosed at any age with:

    • ≥1 close blood relative with:

      • Breast cancer diagnosed at age ≤50 years; or

      • Ovarian carcinoma; or

      • Metastatic or intraductal/cribriform prostate cancer, or high-risk group or very-high-risk group (see Policy Guidelines) prostate cancer; or

      • Pancreatic cancer; or

    • ≥3 total diagnoses of breast cancer in individual and/or close blood relatives; or

    • Ashkenazi Jewish ancestry

  • Diagnosed at any age with male breast cancer

• Personal history of epithelial ovarian carcinoma (including fallopian tube cancer or peritoneal cancer) at any age

• Personal history of exocrine pancreatic cancer at any age

• Personal history of metastatic or intraductal/cribriform histology prostate cancer at any age; or high-risk group or very-high-risk group prostate cancer at any age

• Personal history of prostate cancer at any age with:

  • ≥1 close blood relative with ovarian carcinoma, pancreatic cancer, or metastatic or intraductal/cribriform prostate cancer at any age, or breast cancer at age ≤50 years; or

  • ≥2 close blood relatives with breast or prostate cancer (any grade) at any age; or 

  • Ashkenazi Jewish ancestry

• Personal history of a BRCA1, BRCA2, or PALB2 pathogenic/likely pathogenic variant identified on tumor genomic testing that has clinical implications if also identified in the germline.

Individuals Without Cancer or With Other Personal History of Cancer

(See Policy Guidelines section: Testing Unaffected Individuals.)

Genetic testing for BRCA1,BRCA2, and PALB2 variants of cancer-unaffected individuals and individuals with cancer but not meeting the above criteria (including individuals with cancers unrelated to hereditary breast and ovarian cancer syndrome) may be considered medically necessary under any of the following circumstances:

• An individual with or without cancer and not meeting the above criteria but who has a 1st- or 2nd-degree blood relative meeting any criterion listed above for Patients With Cancer (except individuals who meet criteria only for systemic therapy decision-making). If the individual with cancer has pancreatic cancer or prostate cancer (metastatic or intraductal/cribriform or high-risk group or very-high-risk group) then only first-degree relatives should be offered testing unless there are other family history indications for testing.

• An individual with any type of cancer (cancer related to hereditary breast and ovarian cancer syndrome but not meeting above criteria, or cancer unrelated to hereditary breast ovarian cancer syndrome) or unaffected individual who otherwise does not meet the criteria above but has a probability >5% of a BRCA1/2 or PALB2 pathogenic variant based on prior probability models (eg, Tyrer-Cuzick, BRCAPro, Pennll).

Genetic testing for BRCA1 and BRCA2 variants of cancer-affected individuals or cancer-unaffected individuals with a family history of cancer when criteria above are not met is considered investigational.

Testing for PALB2 variants in individuals who do not meet the criteria outlined above is considered investigational.

Genetic testing in minors for BRCA1,BRCA2, and PALB2 variants for hereditary breast and ovarian cancer syndrome is considered investigational (see Policy Guidelines).

POLICY EXCEPTIONS

None

POLICY GUIDELINES

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

There are differences in the policy statements above and the National Comprehensive Cancer Network (NCCN) guideline on Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (v.3.2025). Not all of the NCCN criteria are clearly separated for determining hereditary breast and ovarian cancer syndrome versus for guiding therapy. Testing for BRCA1, BRCA2, and/or PALB2 outside of the above criteria, such as testing all individuals with triple negative breast cancer or testing all individuals diagnosed with breast cancer under the age of 50 years, may be indicated for guiding cancer therapies. Genetic testing for BRCA1 and BRCA2 variants in breast cancer-, pancreatic cancer-, prostate cancer-, or ovarian cancer-affected individuals who are considering systemic therapy is addressed separately in the following policies: Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer, Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53), Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, Microsatellite Instability/Mismatch Repair, Tumor Mutational Burden) , and Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, Tumor Mutational Burden, Microsatellite Instability/Mismatch Repair) , respectively. Genetic testing for PALB2 variants in pancreatic cancer-affected individuals is also addressed in the Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53) medical policy. Additionally, conflicting criteria reflect that some of the NCCN criteria are based on limited or no evidence; the lower level of evidence might be needed when determining coverage of testing mandated by state biomarker legislation.

Current U.S. Preventive Services Task Force guidelines recommend screening women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutation. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing (B recommendation).

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)

• International Breast Cancer Intervention Study instrument (Tyrer-Cuziak)

• Brief versions of the BRCAPRO

Close Relatives

Close relatives are blood related family members including 1st-, 2nd-, and 3rd-degree relatives on the same side of the family (maternal or paternal).

• 1st-degree relatives are parents, siblings, and children.

• 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.

• 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins.

Prostate Cancer Risk Groups

Risk groups for prostate cancer in this policy include high-risk groups and very-high-risk groups.

High-risk group: no very-high-risk features and are T3a (American Joint Committee on Cancer staging T3a = tumor has extended outside of the prostate but has not spread to the seminal vesicles); OR Grade Group 4 or 5; OR prostate specific antigen of 20 ng/mL or greater.

Very-high-risk group: T3b-T4 (tumor invades seminal vesicle(s); or tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall); OR Primary Gleason Pattern 5; OR 2 or 3 high-risk features; OR greater than 4 cores with Grade Group 4 or 5.

Recommended Testing Strategies

Individuals who meet criteria for genetic testing as outlined in the policy statements above should be tested for variants in BRCA1,BRCA2, and PALB2. Recommended strategies are listed below.

• In individuals with a known familial BRCA or PALB2 variant, targeted testing for the specific variant is recommended.

• In individuals with unknown familial BRCA or PALB2 variant:

  • To identify clinically significant variants, National Comprehensive Cancer Network (NCCN) advises testing a relative who has early-onset disease, bilateral disease, or multiple primaries, because that individual has the highest likelihood of obtaining a positive test result. Unless the affected individual is a member of an ethnic group for which particular founder pathogenic or likely pathogenic variants are known, comprehensive genetic testing (ie, full sequencing of the genes and detection of large gene rearrangements) should be performed.

  • 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 or BRCA2 variants (eg, prostate cancer, pancreatic cancer, melanoma).

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

• Full sequencing of BRCA1 and BRCA2 followed by testing for 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 large genomic rearrangements (also known as comprehensive BRCA testing; see Comprehensive Variant Analysis below) may be performed as is recommended by the NCCN.

  • Comprehensive testing can detect 92.5% of BRCA1 or BRCA2 variants.

• Testing for BRCA1, BRCA2, and PALB2 through panel testing over serial testing might be preferred for efficiency. Multi-gene panels often include genes of moderate or low penetrance, and genes with limited evidence on which to base management decisions. When considering a gene panel, NCCN recommends use of "tailored panels that are disease-focused and include clinically actionable cancer susceptibility genes".

• Ashkenazi Jewish descent

  • In individuals of known Ashkenazi Jewish descent, one approach is to test for the 3 known founder mutations (185delAG and 5182insC in BRCA1; 6174delT in BRCA2) first. If testing is negative for founder mutations and if the individual’s ancestry also includes non-Ashkenazi ethnicity (of if other BRCA1/2 testing criteria are met), comprehensive genetic testing should be considered.

Testing strategy may also include testing individuals not meeting the above criteria who are adopted and have limited medical information on biological family members, individuals with small family structure, and individuals with presumed paternal transmission.

Comprehensive Variant Analysis

Comprehensive variant analysis currently includes sequencing the coding regions and intron and exon splice sites, as well as testing to detect large deletions and rearrangements that can be missed with sequence analysis alone. In addition, before August 2006, testing for large deletions and rearrangements was not performed, thus some individuals with familial breast cancer who had negative BRCA testing before this time may consider repeat testing for the rearrangements (see Policy statement 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.

Testing Unaffected Individuals

In unaffected family members of potential BRCA or PALB2 variant 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 or PALB2 variant be found in an affected family member(s), DNA from the unaffected family member can be tested specifically for the same variant 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 variant but leads to difficulties in interpreting negative test results (uninformative negative) or variants of uncertain significance because the possibility of a causative BRCA or PALB2 variant is not ruled out.

Testing for known variants of BRCA or PALB2 genes in an unaffected reproductive partner may be indicated as carrier screening for rare autosomal recessive conditions.

Testing Minors

The use of genetic testing for BRCA1, BRCA2, or PALB2 variants for identifying hereditary breast and ovarian cancer syndrome has limited or no clinical utility in minors, because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious variant. In addition, there are potential harms related to stigmatization and discrimination. See the following policies: Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53) , Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer, Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, Microsatellite Instability/Mismatch Repair, Tumor Mutational Burden), and Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, Tumor Mutational Burden, Microsatellite Instability/Mismatch Repair) regarding genetic testing to guide targeted therapy.

Prostate Cancer

Individuals with BRCA or PALB2 variants have an increased risk of prostate cancer, and individuals with known BRCA or PALB2 variants may, therefore, consider more aggressive screening approaches for prostate cancer.

Genetics Nomenclature Update

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

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

Table 1. Nomenclature to Report on Variants Found in DNA

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

ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Genetic Counseling

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

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

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

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

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

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

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

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

POLICY HISTORY

2/2001: Approved by Medical Policy Advisory Committee (MPAC)

2/12/2002: Investigational definition added

3/8/2002: Case-by-case consideration deleted

5/1/2002: Type of Service and Place of Service deleted.

5/14/2002: Code Reference section updated; ICD-9 diagnosis codes V10.3 and V10.43 deleted

1/30/2003: Medically necessary verbiage added to "Policy" section

6/12/2003: Code Reference section updated

7/2003: Reviewed by MPAC, "Genetic counseling is required by a board certified geneticist." deleted, minors age changed to 18Code Reference section updated, CPT code range 83890-83906 listed separately, ICD-9 diagnosis code range 174.0-174.9, 175.0-175.9 listed separately, FEP exception added

7/30/2004: Code Reference section updated, ICD-9 diagnosis code V10.3, V10.43 added

11/11/2005: Code Reference section updated, 5th digit added to ICD9 diagnosis code V26.31, description revised

3/28/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy. 

9/12/2006: Coding updated. ICD9 2006 revisions added to policy.

12/28/2006: Code Reference section updated per the 2007 CPT/HCPCS revisions

7/20/2007: Policy reviewed. Genetic testing for individuals with early onset breast or ovarian cancer without a known family history, and unaffected individuals from families with a high risk of BRCA1 or BRCA2 mutation based on family history where it is not possible to test an affected member added as may be medically necessary. Genetic testing of unaffected individuals of potentially high-risk populations (e.g. Ashkenazi Jewish descent) changed from investigational to may be medically necessary. HCPCS S3823 moved to covered. Non-covered codes table removed. FEP exceptions removed

9/12/2007: Code reference section updated per the annual ICD-9 updates effective 10-1-2007

12/19/2007: Coding updated per the 2008 CPT/HCPCS revisions

2/26/2008: Policy description updated. Policy statements revised. Added genetic testing of cancer affected women with breast or ovarian cancer with no family history, women affected with both breast and ovarian cancer, men affected with breast cancer at any age maybe medically necessary in cancer-affected individuals. Policy statements clarified for cancer-affected and unaffected individuals from a high risk ethnic background (Ashkenazi Jewish descent). Clarifiedinvestigational policy statement for genetic testing in unaffected individuals and those not meeting policy criteria. Policy title changed from "Genetic Testing for Inherited BRCA1 or BRCA2 Mutations" to "Genetic Testing for Hereditary Breast and/or Ovarian Cancer"

12/24/2008: Coding Reference section updated per 2009 CPT/HCPCS revisions

2/3/2009: Policy statement and policy guideline section updated.

07/30/2010: Policy Description section was revised to add fallopian tube and primary peritoneal cancers. Information about CHEK2 was also added. Policy Statement section was revise to add fallopian tube or primary peritoneal cancers and testing for CHEK2 genetic abnormalities (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer irrespective of the family history. Policy Guidelines section was revised to add fallopian tube and primary peritoneal cancers. CPT codes 88271 - 88275 and 88291 were added to the Covered Codes Table. ICD-9 Diagnosis code 233.3 was removed from table (deleted 9-30-2007) and 233.39 was added to Covered Codes Table; however, V26.35 was removed from the Covered Codes Table.

02/24/2012: Policy statement regarding CHEK2 revised to state the following: Testing for mutations other than BRCA1 and BRCA2, such as the CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer irrespective of the family history. It previously stated the following: Testing for CHEK2 genetic abnormalities (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer irrespective of the family history. Deleted outdated references from the Sources section.

07/19/2012: The second bullet in the first policy statement was re-written. Added the following medically necessary policy statement: Testing for genomic rearrangements of the BRCA1 and BRCA2 genes may be considered medically necessary in patients who meet criteria for BRCA testing, whose testing for point mutations is negative and either (1) there are 3 or more family members (one lineage) affected with breast or ovarian or fallopian tube or primary peritoneal cancer or (2) who have a risk of a BRCA mutation of at least 10%. Updated the policy guidelines regarding high risk criteria. Added CPT codes 81211 - 81217 to the Code Reference section.

02/20/2013: Policy statement regarding coverage of testing for epithelial ovarian/fallopian tube/primary peritoneal cancer clarified. Additional medical necessary statement for testing added for women with breast cancer and two or more close relatives with pancreatic cancer. The policy statement regarding testing for genomic rearrangements was revised to delete the following requirements: and either (1) there are 3 or more family members (one lineage) affected with breast or ovarian or fallopian tube or primary peritoneal cancer or (2) who have a risk of a BRCA mutation of at least 10%.

04/07/2014: Policy statement updated to add "including those with a family history of pancreatic cancer" to the investigational statement. Removed deleted CPT Codes 83890 - 83894, 83896 - 83898, 83900 - 83909, and 83912 - 83914 from the Code Reference section.

08/28/2015: Medical policy revised to add ICD-10 codes. Removed ICD-9 procedure code 99.99 from the Code Reference section. Removed the following deleted HCPCS codes: S3818, S3819, S3820, S3822, and S3823.

12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to add new 2016 CPT code 81162.

06/08/2016: Policy number A.2.04.02 added.

12/20/2018: Code Reference section updated to add new 2019 CPT codes 81163, 81164, 81165, 81166, and 81167. Revised code descriptions for CPT codes 81162, 81212, 81215, 81216, and 81217.

01/31/2020: Policy title changed from "Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome (BRCA1/BRCA2)" to "Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers." Policy description updated regarding clinical features suggestive of BRCA variant. Added information regarding laboratory testing. CHEK2 removed from policy description and policy statements. Medically necessary statements updated to reflect changes to the NCCN recommendation. Removed medically necessary statement regarding testing for genomic rearrangements and added recommended testing strategies to the Policy Guidelines section. Policy Guidelines updated regarding current USPSTF guidelines. Added information regarding testing minors, prostate cancer, and genetic counseling. Code Reference section updated to add ICD-10 diagnosis codes C25.0 - C25.9, C61, Z85.07, and Z85.46. Removed deleted CPT codes 81211, 81213, and 81214.

02/12/2020: Code Reference section updated to add CPT code 0138U and diagnosis codes Z85.068, Z85.09, Z85.49, Z80.0, and Z80.42.

06/22/2020: Code Reference section updated to add new CPT code 0172U, effective 07/01/2020.

10/01/2021: Code Reference section updated to add new ICD-10 diagnosis code C79.63, effective 10/01/2021.

03/23/2022: Policy title changed from “Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers” to “Germline Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers.” Policy description updated regarding FDA approved companion diagnostics and Poly (Adenosine Diphosphate-Ribose) Polymerase (PARP) inhibitors. Policy statements revised to reflect current NCCN guidelines. Policy Guidelines updated to add information regarding close relatives, breast cancer risk groups, prostate cancer risk groups, recommended testing strategies, and genetics nomenclature. "Nervous/Mental Conditions" changed to "Mental Health Disorders" and "Medically Necessary" changed to "medical necessity."

03/01/2023: Policy title changed from "Germline Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers" to "Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)." Policy description updated to add information regarding the PALB2 gene (previously found in medical policy A.2.04.126). Removed information regarding FDA approved companion diagnostics for PARP inhibitors. Policy statements updated to change "patients" to "individuals" and to include PALB2 variants as medically necessary when meeting the specified criteria. Medically necessary statement criteria updated to remove content on the use of BRCA1 and BRCA2 variant testing in breast cancer-affected individuals who are considering systemic therapy options. Policy Guidelines updated to add links to related policies and to add information regarding recommended testing strategies, testing unaffected individuals, testing minors, and prostate cancer. Removed information regarding breast cancer risk groups. Code Reference section updated to add CPT codes 81307 and 81308.

09/08/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding NCCN guidelines and testing unaffected individuals.

11/22/2024: Policy reviewed. Revised policy statement regarding personal history of genetic mutations. It previously stated: Personal history of cancer and a mutation identified on tumor genomic testing that has clinical implications if also identified in the germline. Policy Guidelines updated with minor changes.

12/31/2024: Code Reference section updated to make note of deleted CPT code 96040.

09/16/2025: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding NCCN guideline.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes C50.A0, C50.A1, C50.A2, Z85.4A, and Z86.00A.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.02

CODE REFERENCE

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

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

Covered Codes

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