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Germline mutations in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in the majority of HBOC families, especially if ovarian cancer or male breast cancer are features. However, in site-specific breast cancer, BRCA mutations are responsible for only a proportion of affected families, and research to date has not yet identified other moderate or high-penetrance gene mutations that account for disease in these families. BRCA gene mutations 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 mutation in cancer cases, and to identify family members with increased cancer risk. Family members without existing cancer who are found to have BRCA mutations can consider preventive interventions for reducing risk and mortality.

CHEK2 (cell cycle checkpoint kinase2) is also involved with DNA repair and human cancer predisposition like BRCA1 and BRCA2. CHEK2 is normally activated in response to DNA double-stranded breaks. CHEK2 regulates the function of BRCA1 protein in DNA repair and also exerts critical roles in cell cycle control and apoptosis. The CHEK2 mutation, 1100delC in exon 10 has been associated with familial breast cancers. 

• Women who are affected with breast cancer or pancreatic cancer, and are from families with a high risk of BRCA1 or BRCA2 mutation as defined in the Policy Guidelines, OR;
• Women who are affected with breast cancer or pancreatic cancer who are not from families with a high risk of BRCA1 or BRCA2 mutation, as defined in the Policy Guidelines, but are affected with any of the following:
  • early onset breast cancer
  • two breast primary cancers with the first cancer diagnosis occurring prior to age 50 years;
  • triple negative breast cancer (neither express estrogen receptor and progesterone receptor, nor overexpress HER2) diagnosed at younger than age 60;
  • two or more close blood relatives with pancreatic cancer at any age
• Women affected with epithelial ovarian cancer/fallopian tube /primary peritoneal cancer, OR;
• Men affected with breast cancer at any age, OR;
• Those affected with breast cancer who are from an ethnic background, e.g., Ashkenazi Jewish descent, associated with deleterious founder mutations.

Genetic testing for BRCA1 and BRCA2 mutations of unaffected adults may be considered medically necessary under any of the following circumstances:

• Unaffected individuals (male or female) from families with a known BRCA1 or BRCA2 mutation, OR;
• Unaffected individuals from families with a high risk of BRCA1 or BRCA2 mutation based on a family history (see Policy Guidelines), where it is not possible to test an affected family member for a mutation.
• Unaffected individuals in populations at risk for specific founder mutations due to ethnic background, e.g., Ashkenazi Jewish descent, and with one or more relatives with breast, epithelial ovarian, fallopian tube, or primary peritoneal cancer at any age.

Further, the genetic testing should be performed in a setting that has suitably trained healthcare providers who can give appropriate pre- and post-test counseling and that has access to a CLIA-licensed laboratory that offers comprehensive mutation analysis (see Policy Guidelines).

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.

Unless they meet the criteria above, genetic testing for either those affected with breast, ovarian, fallopian tube, or primary peritoneal cancer or for unaffected individuals is considered investigational.

Testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of the family history.

Genetic testing in minors for BRCA1 and BRCA2 mutations is investigational.

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

In identifying families with a high risk of mutation in the BRCA1 or BRCA 2 gene, both maternal and paternal family histories are important, but each lineage must be considered separately. Any of the following scenarios indicates a high risk of BRCA1 or BRCA2 mutation. In assessing risk of a mutation for those affected with cancer, the overall family history (one lineage) including the affected person is considered. The following criteria for non-Ashkenazi Jewish women unaffected with cancer were derived by the USPSTF in 2005 after extensive literature review by the U.S. Preventive Services Task Force (USPSTF):

• Three or more first or second degree relatives with breast cancer regardless of age at diagnosis; or
• Two first degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or
• Combination of both breast and ovarian or fallopian tube or primary peritoneal cancer among first- and second degree relatives; or
• First degree relative with bilateral breast cancer; or
• A combination of two or more first or second degree relatives with ovarian or fallopian tube or primary peritoneal cancer regardless of age at diagnosis; or
• A first or second degree relative with both breast and ovarian or fallopian tube or primary peritoneal cancer at any age; or
• A history of breast cancer in a male relative.

More recent definitions of high-risk have been published, including the 2011 revised recommendations from National Comprehensive Cancer Network (NCCN). The following high-risk criteria largely represent NCCN hereditary breast and/or ovarian cancer syndrome testing criteria with some modifications based on additional guidelines and review of evidence.

A personal or family history suggesting genetic cancer susceptibility requires at least one of the following criteria to be present: 

• Individual from a family with a known deleterious BRCA1/BRCA2 mutation
• Personal history of breast cancer plus one or more of the following:
  • Diagnosed at an early age (see definition, following)
  • Diagnosed at age <50 years with at least one close blood relative (see definition, following) with breast cancer at age <50 years and/or at least one close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
  • Two breast primaries when the first breast cancer diagnosis occurred prior to age 50 years
  • Diagnosed age <60 years with a triple negative breast cancer
  • Diagnosed age <50 years with a limited family history
  • Diagnosed at any age, with >2 close blood relatives with breast and/or epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
  • Close male relative with breast cancer
  • Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer
  • For an individual of ethnicity associated with higher mutation frequency (e.g., Ashkenazi Jewish) no additional family history may be required
• Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer
• Personal history of male breast cancer
• Personal history of breast and/or ovarian cancer at any age with >2 close blood relatives with pancreatic cancer at any age
• Personal history of pancreatic cancer at any age with >2 close blood relatives with breast and/or ovarian cancer and/or pancreatic cancer at any age
• Family history only:
  •  Close blood relative meeting any of the above criteria

Early age at diagnosis refers generally to diagnosis before age 40 to 45 years; an exact cutoff for testing affected individuals without known family history but with cancer diagnosis at an early age has not been established, although guidelines of the American College of Medical Genetics suggest age 45 or younger (see Rationale). The decision to test an affected individual based on age at diagnosis in the absence of family history will depend on the risk estimate for the individual patient (e.g., from widely available risk assessment computer programs) and the patient tolerance for risk, and the desire to inform the risk of family members.

Definition: Close blood relative typically refers to first degree (parent, full sibling, or offspring) and second degree (grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling) relatives in diseases associated with high penetrance gene mutations such as BRCA1 and BRCA2 mutations. Accommodation may be made to include third degree relatives (first cousin, great grandparent or great grandchild) in some cases, e.g., limited family history, particularly in tracing hereditary breast and ovarian and related cancers in the paternal lineage. Certified genetic counselors or other qualified genetics professionals are best able to assess exceptional cases.

As the majority of test results will be negative and uninformative in unaffected family members of potential BRCA mutation families, 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), the DNA from the unaffected family member can be tested specifically for the same mutation of the affected family member without having to sequence the entire gene. Interpreting the 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 or mutations of uncertain significance because the possibility of a causative BRCA mutation is not ruled out.

In patients with breast cancer, ovarian cancer, cancer of the fallopian tube, or primary peritoneal cancer who are from high-risk families without a known BRCA1 or BRCA2 gene and who are not from ethnic groups with known founder mutations, comprehensive BRCA mutation analysis should be performed.

Testing in eligible individuals who belong to ethnic populations in which there are well-characterized founder mutations should begin with tests specifically for these mutations. For example, founder mutations account for approximately three quarters of the BRCA mutations found in Ashkenazi Jewish populations (see Rationale). When the testing for founder mutations is negative, comprehensive mutation analysis should then be performed.

Comprehensive mutation 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. However, current routine laboratory testing for genomic rearrangement is more limited than the criteria noted in the policy statement; automatic testing is specified for those with a risk of BRCA mutation of at least 30%. In addition, prior to August 2006, testing for large deletions and rearrangements was not performed, thus some patients with familial breast cancer who had negative BRCA testing prior to this time may consider repeat testing for the rearrangements (see Policy statement for criteria). These rates are calculated using the Myriad II risk model (Available online at: www.myriadtests.com).

As noted above, cancers of the fallopian tube and primary peritoneal cancer are also considered BRCA-associated malignancies and are to be considered along with breast and ovarian cancer in assessing the family history.

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). Clarified investigational 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 statment 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%.  

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

Covered Codes

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