CAM 261

BRCA

Category:Laboratory   Last Reviewed:April 2021
Department(s):Medical Affairs   Next Review:April 2022
Original Date:July 1997    

Description
BRCA1 and BRCA2 are two distinct tumor suppressor genes involved in a common DNA repair process (Roy, Chun, & Powell, 2012). Germline mutations of BRCA genes are associated with an increased risk of breast and ovarian cancer, as well as other cancer types, including pancreatic and prostate cancer to a lesser extent (Paul & Paul, 2014).

Regulatory Status
The Center for Devices and Radiological Health of the Food and Drug Administration (FDA, 2018) granted premarket approval on 1/12/2018 to BRACAnalysis CDx® is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Another FDA-approved device is the “FoundationFocus CDxBRCA”, which is a “is a next generation sequencing based in vitro diagnostic device for qualitative detection of BRCA1 and BRCA2 alterations in formalin-fixed paraffin-embedded (FFPE) ovarian tumor tissue”. This test is intended to be used “as an aid in identifying ovarian cancer patients for whom treatment with Rubraca (rucaparib) is being considered” (FDA, 2016). A more recent FDA-approved device comes out of Myriad Genetics, Inc., the myChoice HRD CDx, which was approved on October 23, 2019. This test is a “next generation sequencing-based in vitro diagnostic test that assesses the qualitative detection and classification of single nucleotide variants, insertions and deletions, and large rearrangement variants in protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes and the determination of Genomic Instability Score (GIS)” based off tumor tissue specimens.

Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

Consideration of both maternal and paternal family histories is necessary in the evaluation of individuals for risk of carrying a mutation in the BRCA1 or BRCA2 gene; each lineage must be considered separately.  

  1. BRCA 1 and 2 testing should be offered for individuals meeting any of the criteria described in 2 through 4 below if the individual
    1. Has received genetic counseling AND
    2. Is at least 18 years of age.
  2. BRCA 1 and 2 testing in an individual from a family with a known deleterious BRCA1/BRCA 2 gene mutation is considered MEDICALLY NECESSARY and is limited to the known familial mutation.
  3. If the specific familial mutation is unknown, testing for large genomic rearrangements of BRCA1 and/or BRCA2 is considered MEDICALLY NECESSARY.
  4. BRCA 1 and BRCA 2 testing is considered MEDICALLY NECESSARY when an individual with cancer meets any of the following criteria:
    1. Diagnosed with breast cancer and at least one of the following:
      1. Diagnosed at age < 45 years of age; or
      2. Diagnosed between ages 46 and 50 years and one of the following:
        1. An additional breast cancer diagnosed at any age; or
        2. At least one close blood relative (See Note 1) with breast, ovarian, pancreatic, or prostate cancer at any age; or
        3. An unknown or limited family history (e.g. adopted or fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage)
      3. Diagnosed with breast cancer at age < 60 years and triple negative breast cancer (estrogen receptor/ ER negative, progesterone receptor/ PR negative and human epidermal growth factor/HER-2 negative)
      4. Diagnosed at any age and one of the following:
        1. Ashkenazi Jewish ancestry; or
        2. At least one close blood relative (See Note 1) with breast cancer at age <50 y or ovarian, pancreatic, or high- or very-high risk group (see Note 4) prostate cancer at any age (defined as Gleason score 8 or higher, PSA 20 or higher, intraductal/cribriform histology, or stage III or higher i.e. extends through prostate capsule)
        3. A combined total of at least three diagnoses of breast cancer in patient and/or close blood relatives (See Note 1)
      5. Diagnosed at any age with male breast cancer
    2. Has a history of ovarian cancer (including fallopian tube cancer or peritoneal cancer) at any age (excluding germ cell cancers)
    3. Has a history of pancreatic cancer at any age (excluding neuroendocrine pancreatic cancer)
    4. Has a history of prostate cancer at any age with one of the following:
      1. Has a history of high- or very-high-risk group (See Note 2) prostate cancer at any age (defined as Gleason score 8 or higher, PSA 20 or higher, intraductal/cribriform histology, or stage III or higher i.e. extends through prostate capsule)
      2. Any personal history of prostate cancer (See Note 2) with the following family history:
        1. Is of Ashkenazi Jewish ancestry; or
        2.  >1 close blood relative (See Note 1) with breast cancer at age ≤50 years or ovarian, pancreatic, metastatic or intraductal/cribriform prostate cancer at any age; or
        3. Two or more close blood relatives (See Note 1) with either breast or prostate cancer of any grade at any age
    5. Has a BRCA 1 or 2 mutation detected by tumor genomic profiling in the absence of germline mutation testing
    6. Patient is being considered for treatment with a PARP (PolyADP-ribose polymerase) inhibitor or for platinum therapy
  5. Testing for individuals without cancer (note the significant limitation interpreting test results in persons unaffected by cancer) is considered MEDICALLY NECESSARY ONLY if family members affected by breast, ovarian, pancreatic, metastatic or intraductal prostate cancer, fallopian tube, or primary peritoneal cancers are not available for testing AND:
    1. Individual has a first- or second-degree blood relative meeting any of the above criteria for individual with cancer (if the affected relative has pancreatic or high-risk or very high-risk prostate cancer only first-degree relatives should be offered testing unless indicated for other relatives based on additional family history); or
    2. Individual who has family members with breast, ovarian, tubal, or peritoneal cancer with positive screening results (probability of 5% or greater) from a tool (see Note 3) 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)
    3. An Ashkenazi Jewish individual (see Note 4)
  6. Testing for BRCA 1 and BRCA 2 is considered NOT MEDICALLY NECESSARY for the following:    
    1. Genetic testing in minors < 18 years of age
    2. General population screening
    3. Women diagnosed with breast cancer at age > 65 y, with no close relative (see Note 1) with breast, ovarian, pancreatic, or prostate cancer as there is a low probability that testing will have findings of documented clinical utility
    4. Men diagnosed with localized prostate cancer with Gleason Score <7 and no close relative (see Note 1) with breast, ovarian, pancreatic, or prostate cancer as there is a low probability that testing will have findings of documented clinical utility
    5. In all other situations not specified above

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Testing family members for a variant of unknown significance is considered NOT MEDICALLY NECESSARY.

Note 1: Close blood relatives include 1st-degree relatives (e.g., parents, siblings, and children), 2nd-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and 3rd-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins), all of whom are on the same side of the family.

Note 2: Risk groups are defined in NCCN Guidelines for Prostate Cancer https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

Note 3: According to the USPSTF recommendation in 2019, the risk tools evaluated by the USPSTF include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, International Breast Cancer Intervention Study instrument (Tyrer-Cuzick), and brief versions of BRCAPRO. They do not specifically state the preference of one tool over any of the others listed. According to the USPSTF, “these tools should be used to guide referrals to genetic counseling” (USPSTF, 2019).

Note 4: Testing of Ashkenazi Jewish individuals without a known familial mutation should be initially limited to the three known founder mutations (185delAG and 518insC in BRCA1; 617delT in BRCA2) if the patient being tested has no personal or family history of BRCA-related cancers.

(This would allow for members with cancer and strong family history to start with comprehensive testing over founder mutations)

Note 5: For multi-gene next generation sequencing panel testing that includes BRCA1 and BRCA2 please refer to AHS-M2066-Genetic Cancer Susceptibility Using Next Generation Sequencing.

Rationale
BRCA1 and BRCA2 are critical genes in the process of homologous recombination repair of double-strand DNA breaks (Walsh, 2015). Both genes are very large (occupying about 70 kb) and encode a combined total of 49 exons. They are considered tumor suppressor genes and a loss of function on either gene increases the cancer risk (Pan & Xie, 2017). BRCA1 is thought to regulate c-Abl kinase activity (as loss of BRCA1 results in a constitutively activated c-Abl kinase) whereas BRCA2 is thought to regulate Rad51, which repairs DNA damage such as chromosomal breaks (Yoshida & Miki, 2004).

Different regions of mutation may confer different types of risk. For example, BRCA2 has an area called the ovarian cancer cluster region (OCCR) in which mutations predispose the patient for ovarian cancer. Mutations outside the OCCR are more likely to result in breast cancer compared to mutations in the OCCR. On BRCA1, mutations closer to the 3’ end of the gene may result in higher risk than mutations closer to the 5’ end (Meric-Bernstam et al., 2013). Other gene defects that affect homologous recombination include hypermethylation of RAD51C or ATR mutation. However, these are considered to have a phenotype of “BRCAness” and behave like BRCA-deficient genes even if the BRCA gene itself is normal (Walsh, 2015).

The overall prevalence of disease related mutations in these genes is estimated to be 1 in 300 for BRCA1 and 1 in 800 for BRCA2 (NCCN, 2020b). Although the probability of cancer development in carriers is variable, estimates of penetrance in individuals with a pathogenic variant in BRCA1 or BRCA2 range from 46% to 87% lifetime risk for breast cancer, and 16.5% to 63% lifetime risk for ovarian cancer (Petrucelli, Daly, & Pal, 2016). BRCA1 and BRCA2 mutations account for about 5 – 10% of breast cancers and 10 – 18% of ovarian cancers (Walsh, 2015). BRCA mutations are inherited in an autosomal dominant fashion and are highly penetrant (Isaacs & Peshkin, 2020).

It is clinically important to recognize these carriers to guide management of cancer and identify unaffected women with a BRCA mutation who will benefit from enhanced surveillance, tailor care to improve outcomes, and more efficiently use health-care resources. This has the potential to have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk (Buchanan et al., 2017). For example, BRCA deficient cancers are often targeted for a certain class of drugs called poly(ADP-ribose) polymerase (PARP) inhibitors. These inhibitors target enzymes responsible for the base excision repair pathway. A cell can survive with the loss of either the base excision repair pathway or the homologous recombination mechanism, but not both. Since BRCA-deficient cells already have a faulty homologous recombination mechanism, the BRCA-deficient cell dies when the PARP inhibitor shuts down the base excision repair pathway. BRCA-deficient cells have been shown to be affected 1,000 times more by these PARP inhibitors than wild-type cells (Walsh, 2015).

Numerous proprietary tests exist for the assessment of BRCA or its related genes such as RAD51. For example, gene panels such as Ambry Genetics’ panel include 25 genes such as BRCA1, BRCA2, CHEK2, ATM, RAD51C, and BRIP1. This test is performed by next generation sequencing or Sanger sequencing (except for EPCAM) with a turnaround time of 2-3 weeks. Ambry has several proprietary tests such BRCAplus and BreastNext (Ambry, 2020). Another gene panel that has been developed to identify genetic mutations associated with inherited breast and ovarian cancers is the AmpliSeq for Illumina BRCA Plus, Extended Hereditary Breast and Ovarian Research Panel. This panel assesses germline variants in 11 genes known to harbor mutations related to breast and ovarian cancer: ATMBRCA1BRCA2CHEK2PALB2RAD51CRAD51DNBNCDH1SMARCA4, and TP53. However, though these community panels boasts the convenience of being made-to-order, Illumina warns that they do not have associated performance metrics (Illumina, 2021). myChoice CDx by Myriad Genetics, Inc. is a tumor test that determines homologous recombination deficiency status by detecting BRCA1 and BRCA2 (sequencing and large rearrangement) variants. This next generation sequencing-based in vitro diagnostic assay focuses on assessing genomic instability by using loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions from tumor tissue specimens. The results can then be used to guide treatment and therapy for ovarian cancer patients with positive homologous recombination deficiency, which is defined by the presence of BRCA1/2 mutations and/or positive Genomic Instability Score (Myriad Genetics, 2021).

Validity and Utility
A study performed by Kuchenbaecker et al. (2017) assessed the cumulative risk of breast and ovarian cancer based on mutation position. A sample of 9,856 patients was analyzed, with 6,036 patients carrying a BRCA1 mutation and 3,820 with a BRCA2 mutation. 5,046 patients were unaffected by either type of cancer and 4,810 had breast cancer, ovarian cancer, or both at baseline. The breast cancer assessment was based on 3,886 carriers, and the ovarian cancer assessment was based on 5,066 women. The authors evaluated the cumulative risk of breast cancer to 80 years to be 72% for BRCA1 mutation carriers and 69% for BRCA2 carriers. Cumulative risk for ovarian cancer to 80 years was found to be 44% for BRCA1 carriers and 17% for BRCA2 carriers. BRCA2 mutations outside the OCCR were found to have a higher risk of breast cancer than mutations inside it (hazard ratio: 1.93 for OCCR ranges 5′ to c.2830, c.2831 to c.6401, c.6402 to 3) but no difference in overall ovarian cancer risk. Mutations closer to the 3’ or 5’ ends of BRCA1 were found to have a higher risk of breast cancer compared to the middle third of the gene and the third closest to the 3’ end had the highest hazard ratio of 1.51 compared to the third closest to the 5’ end (1.43) (Kuchenbaecker et al., 2017).

A meta-analysis of 44 articles was performed to assess the difference in risk factors between BRCA1 and BRCA2 carriers. Factors such as breastfeeding, coffee, infertility, and more were examined between both genotypes, and the only risk factor that revealed an association of any kind was age at first live birth for BRCA1 carriers. Breast cancer risk was found to decrease for BRCA1 women over 30 compared to women under 30, and the same was found for women from 25-29 compared to women under 25. However, the authors stressed that more research was required (Friebel, Domchek, & Rebbeck, 2014).

However, the importance of BRCA testing has not only been explored for lifestyle choices or transient states; factors such as ethnicity can also play a role in the predisposition of patients to breast cancer. Palmer et al. (2020) delved into the risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes. Using germline DNA samples and drawing from 10 epidemiologic studies encompassing 5,054 affected African American women and 4,993 unaffected African American women, Palmer et al. (2020) sequenced mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel and found that pathogenic mutations could be identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with an overall increased risk for breast cancer, while RAD51D mutations were observed specifically to be linked to higher risk of ER-negative disease. Other mutations the researchers found to be of interest were in CHEK2, ATM, ERCC3, FANCC, and RECQL. Thus, it was concluded that the study corroborated the use and “validity of current breast cancer testing panels for use in AA women” (Palmer et al., 2020).

A study using next generation sequencing (NGS) to identify BRCA mutations was performed by Lang et al. 4,034 patients were screened (2,991 breast cancer patients, 1,043 healthy controls). BRCA mutations were found in 247 of the breast cancer patients or 8.3%. 13.9% (16/115) of the BRCA1 mutations were of the “c.5470_5477del” variation, and several clinical characteristics such as high KI67 index and high tumor grade were related to BRCA mutations, BRCA2 carriers were also found to have poorer disease-free survival among HER2 positive patients (Lang et al., 2017).

Tomao et al. (2019) investigated the ability of BRCA mutational status on predicting hematologic toxicity with platinum-based chemotherapy. 176 patients were included, with 58 BRCA mutation carriers (40 BRCA1, 18 BRCA2, 118 controls). The authors identified several differences in hematologic toxicity between the two groups; the BRCA positive group was observed to have significantly higher frequency in “thrombocytopenia (24% vs 5%), anemia (21% vs 7%; p = 0.006) and neutropenia (62% vs 27%)”. The authors also noted that granulocyte-colony stimulating growth factors injection (12% versus 1%,) and dose delay (19% versus 27%) were more likely in the BRCA positive group (odds ratio = 2.567 for granulocyte-colony stimulating growth factors injection and 3.860 for dose delay). Overall, the authors concluded that “germline BRCA 1/2 mutations are associated with a higher hematologic toxicity in patients with ovarian cancer who underwent platinum-based chemotherapy” (Tomao et al., 2019).

Yoo et al. (2020) conducted BRCA1/NGS for 262 hereditary breast and ovarian cancer (HBOC) syndrome patients, and the results were confirmed by using multiplex ligation-dependent probe amplification and direct Sanger sequencing. A multigene panel test was also performed on 120 patients who did not possess BRCA1/2 pathogenic variants but who met NCCN criteria for testing. The researchers reported that pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%), and four out of the 120 patients possessed pathogenic variants of MSH2 PMS2, CHEK2 and PALB2, which were also detectable by multigene panel testing. The results suggested to the authors that “Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer” (Yoo et al., 2020).

BRCA testing has been demonstrated to be potentially beneficial even when the testing is unselected and population based. Manchanda et al. (2020) examined the North London Ashkenazi-Jewish (AJ) population in a randomized controlled trial consisting of 1,034 AJ women and men across two arms—one, a population-screening approach, and a second, a family history/clinical-criteria-based BRCA testing—to determine subsequent effects on psychological health and quality of life after providing genetic testing for three Jewish BRCA founder-mutations. Based on the results of the study, the researchers drew the conclusion that “Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers” (Manchanda et al., 2020). However, these results on the anxiety and health-anxiety of this population may be contested, for validated questionnaires were used to measure the psychological wellbeing of the participants at baseline/1-year/2-year/3-year follow-ups. Moreover, the participants were recruited through self-referral, which may affect the internal validity of the trials.

National Comprehensive Cancer Network (NCCN, 2020a, 2020b, 2020f, 2021a, 2021b)
NCCN guidelines titled Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 2.2021 list the following scenarios as “clinically indicated” for genetic testing:

  1. “Individual with any blood relative with a known pathogenic/likely pathogen variant in a cancer susceptibility gene” (including BRCA1/2)
  2. “Individuals meeting the criteria below but tested negative with previous limited testing, (e.g., single gene and/or absent deletion duplication analysis) that are interested in pursuing multi-gene testing”
  3. Personal history of cancer
    • Breast cancer with at least one of the following:
      • Diagnosed at age ≤45y; or
      • Diagnosed at age 46 – 50y with:
        • Unknown or limited family history; or
        • A second breast cancer diagnosed at any age; or
        • ≥1 close blood relative with breast, ovarian, pancreatic, or prostate cancer
      • Diagnosed at age ≤60 y with triple negative breast cancer;
      • Diagnosed at any age with:
        • Ashkenazi Jewish ancestry; or
        • ≥1 close blood relative with breast cancer diagnosed at age ≤50y, or ovarian, pancreatic, metastatic, intraductal/cribriform histology, or high- or very-high risk group prostate cancer at any age; or
        • ≥3 additional diagnoses of breast cancer in patient and/or in close blood relatives
      • Diagnosed at any age with male breast cancer
    • Epithelial ovarian cancer (including fallopian tube cancer or peritoneal cancer) at any age
    • Exocrine pancreatic cancer at any age
    • Prostate cancer at any age with:
      • Metastatic, intraductal/cribriform histology, or high- or very-high-risk group
    • Any NCCN risk group with the following family history:
      • Ashkenazi Jewish ancestry; or
      • ≥1 close relative with breast cancer at age ≤50y, or ovarian, pancreatic, metastatic or intraductal/cribriform prostate cancer at any age; or
      • ≥2 close relatives with either breast or prostate cancer (any grade) at any age
    • A mutation identified on tumor genomic testing that has clinical implications if also identified in the germline
    • Individual who meets Li-Fraumeni Syndrome (LFS) testing criteria or Cowden syndrome/PTEN hamartoma tumor syndrome testing criteria
    • To aid in systemic therapy decision-making, such as for HER2-negative metastatic breast cancer
  4. Family history of cancer
    • An affected or unaffected individual with a first- or second- degree blood relative meeting any of the criteria listed above (except for individuals who meet criteria only for systemic therapy decision-making)
      • If the affected relative has pancreatic cancer or prostate cancer (metastatic, intraductal/cribriform, or NCCN Guidelines for Prostate Cancer – High- or Very-High-Risk Group), only first-degree relatives should be offered testing unless indicated for other relatives on additional family history.
    • An affected or unaffected individual who otherwise does not meet the criteria above but has a probability >5% of a BRCA1/2 pathogenic variant based on prior probability models (e.g. Tyrer-Cuzick, BRCAPro, CanRisk)

Testing may also be considered in the following scenarios (with appropriate pre-test education and access to post-test management)

  1. Multiple primary breast cancers, first diagnosed between the ages of 50 and 65 y
  2. An Ashkenazi Jewish individual
  3. An affected or unaffected individual who otherwise does not meet any of the above criteria but with a 2.5%-5% probability of a BRCA1/2 pathogenic variant based on prior probability models (e.g. Tyrer-Cuzick, BRCAPro, CanRisk)

There is a low probability (<2.5%) that testing will have findings of documented clinical utility in the following scenarios:

  1. Women diagnosed with breast cancer at age >65 y, with no close relative with breast, ovarian, pancreatic, or prostate cancer
  2. Men diagnosed with localized prostate cancer with Gleason Score <7 and no close relative with breast, ovarian, pancreatic, or prostate cancer (NCCN, 2020d)

The NCCN suggests that prior to genetic testing,

“If more than one family member is affected with cancers highly associated with a particular inherited cancer susceptibility syndrome, consider initial testing of a family member with youngest age at diagnosis, bilateral disease, multiple primary cancers, or other cancers associated with the syndrome, or most closely related to the proband/patient. If there are no available family members with cancer that is a cardinal feature of the syndrome in question, consider testing first- or second-degree family members affected with other cancers thought to be related to the gene in question (e.g., prostate or pancreas with BRCA1/2)” (NCCN, 2020d) 

When there is a known deleterious mutation in a family member, the NCCN recommends that genetic testing in additional family members should be limited to known familial mutations.

In patients with unknown familial BRCA mutation and who meet testing criteria, the NCCN suggests starting testing in the affected family member first because this individual has the highest likelihood of a positive result. NCCN recommends that “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 (i.e. full sequencing of the genes and detection of large gene rearrangements) should be performed by commercial or academic laboratories that are clinically approved or validated” (NCCN, 2020b).

For individuals with family histories consistent with a pattern of hereditary breast and/or ovarian cancer on both the maternal and paternal sides, NCCN states that “the possibility of a second pathogenic or likely pathogenic mutation in the family should be considered, and full sequencing may be indicated, even if a mutation has already been identified in a relative” (NCCN, 2020b, 2020c).

Furthermore, in the situation where the presence of a pathogenic or likely pathogenic variant is unknown, the NCCN recommends that “the testing of the unaffected individual (or of unaffected family members) should only be considered when no affected family member is available for testing. In such cases, the unaffected individual or unaffected close relative with the highest likelihood of testing positive for the pathogenic or likely pathogenic variant should be tested.”, though “A negative test result in such cases, however, is considered indeterminate.” The NCCN also remarks that “testing multiple family members may be indicated” when testing unaffected individuals “(in the absence of having tested affected family members)” to aid in interpreting results (NCCN, 2020d).

NCCN also mentions that “certain large genomic rearrangements are not detectable by a primary sequencing assay, thereby necessitating supplementary testing in some cases… Therefore, the NCCN Guidelines Panel emphasizes the need for comprehensive testing, which encompasses full BRCA1/2 sequencing and detection of large gene rearrangements” (NCCN, 2020b, 2020c).

The NCCN also writes that “In the case of BRCA-related breast/ovarian cancer, if no family member with breast or ovarian cancer is living, consideration can be given testing first- or second-degree family members affected with cancers thought to be related to the pathogenic or likely pathogenic variant in question (e.g. prostate or pancreatic cancer)” (NCCN, 2020b, 2020c).

The NCCN also recommends assessing BRCA1/2 in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy (NCCN, 2020a).

Regarding BRCA in ovarian cancer, the NCCN recommends testing for BRCA1/2 mutations prior to initiating treatment for persistent/recurrent ovarian cancer since “germline and/or somatic BRCA1/2 status informs maintenance therapy.” The NCCN notes that BRCA testing may be done prior to this stage (NCCN, 2020b, 2020e, 2021a).

BRCA testing was also mentioned in guidelines for pancreatic adenocarcinoma. The NCCN recommends tumor/somatic gene profiling for those with “locally advanced/metastatic disease who are candidates for anti-cancer therapy to identify uncommon mutations,” including testing for mutations in BRAF, BRCA1/2, HER2, KRAS, and PALB2 genes, fusions in ALK, NRG1, NTRK, ROS1 genes, and mismatch repair (MMR) deficiency, detected by “tumor IHC [immunohistochemistry], PCR [polymerase chain reaction], or NGS”. NCCN also notes that “Poly (ADP-ribose) polymerase inhibitors provide a promising avenue of treatment for cancers associated with BRCA1/2 mutations” (NCCN, 2020f).

The NCCN also published guidelines regarding BRCA in prostate cancer. Germline genetic testing, which should include BRCA1/2 among other genes, such as ATM, PALB2, and CHEK2 was recommended for initial patients with prostate cancer and any of the following: “a positive family history; high-risk, very-high-risk, regional, or metastatic prostate cancer, regardless of family history; Ashkenazi Jewish ancestry; [and] intraductal histology.” Moreover, the NCCN asserts that “Family history for known germline variants and genetic testing for germline variants should include MLH1, MSH2, MSH6, and PMS2 (for Lynch syndrome) and homologous recombination genes (BRCA1, BRCA2, ATM, PALB2, and CHEK2)”, urging that cancer predisposition next-generation sequencing be considered. However, in general, the NCCN believes that “Genetic testing in the absence of family history or clinical features (e.g., high- or very-high-risk prostate cancer) may be of low yield” (NCCN, 2021b).

With regard to somatic tumor testing in risk groups, “Tumor testing for somatic homologous recombination gene mutations (e.g., BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, CDK12) can be considered in patients with regional (N1) prostate cancer and is recommended for those with metastatic disease.” All testing recommendations should also be considered among those with metastatic castrate-resistant prostate cancer (CRPC) (NCCN, 2021b).

The U.S. Preventive Services Task Force (USPSTF)
In 2019, the USPSTF updated their 2014 recommendation (Moyer, 2014). In it, they state that “ The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with breast cancer susceptibility 1 and 2 (BRCA1/2) gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing.” This recommendation is intended for women with a “personal or family history of breast, ovarian, tubal, or peritoneal cancer or an ancestry associated with BRCA1/2 gene mutation” (USPSTF, 2019).

Moreover, they do not recommend (i.e. issue a D recommendation) routine screening, genetic testing, or genetic counseling for women who have no family or personal history of breast cancer or whose ancestry or ethnicity is not associated with a higher risk for potentially pathogenic BRCA1 or BRCA2 gene mutations (USPSTF, 2019).

The American College of Obstetricians and Gynecologists (ACOG, 2019)
The ACOG in 2019 recommended:

  • Evaluating a patient’s risk of hereditary breast and ovarian cancer syndrome should be a routine part of obstetric and gynecologic practice. Initial risk evaluation should include a personal medical history and family history.
  • Genetic testing is recommended when the results of a detailed risk assessment that is performed as part of genetic counseling suggest the presence of an inherited cancer syndrome for which specific genes have been identified and when the results of testing are likely to influence medical management.
  • The two main genetic testing options for hereditary breast and ovarian cancer syndrome are BRCA mutation testing and multigene panel testing that includes both BRCA and other genetic mutations. Multigene panel testing may be useful when more than one gene may be associated with an inherited cancer syndrome or when a patient has a personal or family history that is consistent with an inherited cancer susceptibility, but single-gene testing has not identified a pathogenic variant.

The American Society of Breast Surgeons (ASBS) (Manahan et al., 2019)
The American Society of Breast Surgeons have released guidelines on genetic testing for hereditary breast cancer. They are as follows:

  1. “Breast surgeons, genetic counselors, and other medical professionals knowledgeable in genetic testing can provide patient education and counseling and make recommendations to their patients regarding genetic testing and arrange testing”
  2. “Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data support that genetic testing should be offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment”
  3. “Patients who had genetic testing previously may benefit from updated testing. Every patient being seen by a breast surgeon, who had genetic testing in the past and no pathogenic variant was identified, should be re-evaluated and updated testing considered. In particular, a patient who had negative germline BRCA1 and 2 testing, who is from a family with no pathogenic variants, should be considered for additional testing.1 Genetic testing performed prior to 2014 most likely would not have had PALB2 or other potentially relevant genes included and may not have included testing for large genomic rearrangements in BRCA1 or BRCA2
  4. “Genetic testing should be made available to patients without a history of breast cancer who meet NCCN guidelines. Unaffected patients should be informed that testing an affected relative first, whenever possible, is more informative than undergoing testing themselves. When it is not feasible to test the affected relative first, then the unaffected family member should be considered for testing if they are interested, with careful pre-test counseling to explain the limited value of “uninformative negative” results. It is also reasonable to order a multi-gene panel if the family history is incomplete (i.e., a case of adoption, patient is uncertain of exact type of cancer affecting family members, among others) or other cancers are found in the family history, as described above.”

American Society of Clinical Oncology (ASCO) (Konstantinopoulos et al., 2020; Tew et al., 2020)
ASCO recommends germline genetic testing for BRCA1/2 for all women diagnosed with epithelial ovarian cancer. Somatic tumor testing for BRCA1/2 should be performed in women that do not carry a germline pathogenic or likely pathogenic variant (Konstantinopoulos et al., 2020).

ASCO also published a guideline regarding PARP inhibitors for ovarian cancer. In recommendation 2.2, they recommend the use of “Myriad myChoice CDx” to determine BRCA1/2 status for therapy decisions (Tew et al., 2020).

National Institute for Health and Care Excellence (NICE, 2019)
NICE updated their guidelines on familial breast cancer in 2019. In it, they maintain their BRCA-related recommendations from 2013, which are as follows:

“Offer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of 10% or more.”

“Offer genetic testing in specialist genetic clinics to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more and an affected relative is unavailable for testing.”

“Offer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more” (NICE, 2019).

European Expert Group (Singer et al., 2019)
A group of 19 experts in BRCA testing were convened to publish this set of guidelines. These experts came from across Europe and Israel, and participants included clinical or medical geneticists (32%), oncologists (37%), and gynaecologists (26%).

The guidelines state that with the rise of next-generation sequencing, hotspot testing instead of complete sequencing is “not acceptable”, albeit noting a possible exception of founder mutations representing >99% of pathogenic variants in a specific area.

A majority of experts (60%) voted that BRCA testing should be offered to all patients with metastatic breast cancer (Singer et al., 2019). 

References 

  1. ACOG. (2019). Practice Bulletin No. 182 Summary: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol, 130(3), 657-659. doi:10.1097/aog.0000000000002285
  2. Ambry. (2020). OvaNext. Retrieved from https://www.ambrygen.com/clinician/genetic-testing/3/oncology/ovanext
  3. Buchanan, A. H., Voils, C. I., Schildkraut, J. M., Fine, C., Horick, N. K., Marcom, P. K., . . . Skinner, C. S. (2017). Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation. J Genet Couns, 26(1), 79-92. doi:10.1007/s10897-016-9981-6
  4. FDA. (2016). FoundationFocus CDxBRCA. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=389050. from FDA https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=389050
  5. FDA. (2018). Premarket Approval (PMA) &#x9;BRACAnalysis CDx. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140020s012. from Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration (FDA) https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140020s012
  6. Friebel, T. M., Domchek, S. M., & Rebbeck, T. R. (2014). Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst, 106(6), dju091. doi:10.1093/jnci/dju091
  7. Illumina. (2021). AmpliSeq for Illumina BRCA Plus, Extended Hereditary Breast and Ovarian Research Panel. Retrieved from https://www.illumina.com/products/by-brand/ampliseq/community-panels/brca-plus-extended-hereditary-breast-ovarian.html
  8. Isaacs, C., & Peshkin, B. N. (2020, 12/1/2020). Cancer risks and management of BRCA1/2 carriers without cancer. Retrieved from https://www.uptodate.com/contents/cancer-risks-and-management-of-brca1-2-carriers-without-cancer
  9. Konstantinopoulos, P. A., Norquist, B., Lacchetti, C., Armstrong, D., Grisham, R. N., Goodfellow, P. J., . . . Annunziata, C. M. (2020). Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. Journal of Clinical Oncology, JCO.19.02960. doi:10.1200/JCO.19.02960
  10. Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K. A., Mooij, T. M., Roos-Blom, M. J., . . . Olsson, H. (2017). Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. Jama, 317(23), 2402-2416. doi:10.1001/jama.2017.7112
  11. Lang, G. T., Shi, J. X., Hu, X., Zhang, C. H., Shan, L., Song, C. G., . . . Shao, Z. M. (2017). The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing. Int J Cancer, 141(1), 129-142. doi:10.1002/ijc.30692
  12. Manahan, E. R., Kuerer, H. M., Sebastian, M., Hughes, K. S., Boughey, J. C., Euhus, D. M., . . . Taylor, W. A. (2019). Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol, 26(10), 3025-3031. doi:10.1245/s10434-019-07549-8
  13. Manchanda, R., Burnell, M., Gaba, F., Desai, R., Wardle, J., Gessler, S., . . . Jacobs, I. (2020). Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes. Bjog, 127(3), 364-375. doi:10.1111/1471-0528.15905
  14. Meric-Bernstam, F., Gutierrez-Barrera, A. M., Litton, J., Mellor-Crummey, L., Ready, K., Gonzalez-Angulo, A. M., . . . Arun, B. K. (2013). Genotype in BRCA-associated breast cancers. Breast J, 19(1), 87-91. doi:10.1111/tbj.12056
  15. Moyer, V. A. (2014). Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 160(4), 271-281. doi:10.7326/m13-2747
  16. Myriad Genetics, I. (2021). What is Myriad myChoice® CDx? Retrieved from https://myriad.com/products-services/precision-medicine/mychoice-cdx/
  17. NCCN. (2020a, 9/8/20). Breast Cancer, V6 2020. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
  18. NCCN. (2020b, 9/8/20). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2021. NCCN Clinical Practice Guidelines in Oncology. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  19. NCCN. (2020c, September 8). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2021. NCCN Clinical Practice Guidelines in Oncology. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  20. NCCN. (2020d, 11/20/2020). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 2.2021. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  21. NCCN. (2020e, 3/11/20). Ovarian Cancer Including Fallopian Tube Cancer and Peritoneal Cancer V1 2020. NCCN Clinical Practice Guidelines in Oncology. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
  22. NCCN. (2020f, October 23 2020). Pancreatic adenocarcinoma V1 2021. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  23. NCCN. (2021a, 1/12/2021). Ovarian Cancer Including Fallopian Tube Cancer and Peritoneal Cancer V2.2020. NCCN Clinical Practice Guidelines in Oncology. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
  24. NCCN. (2021b, 2/2/2021). Prostate Cancer V1.2021. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
  25. NICE. (2019). Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. Retrieved from https://www.nice.org.uk/guidance/cg164/chapter/Recommendations#genetic-testing
  26. Palmer, J. R., Polley, E. C., Hu, C., John, E. M., Haiman, C., Hart, S. N., . . . Couch, F. J. (2020). Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. J Natl Cancer Inst, 112(12), 1213-1221. doi:10.1093/jnci/djaa040
  27. Pan, Z., & Xie, X. (2017). BRCA mutations in the manifestation and treatment of ovarian cancer. Oncotarget, 8(57), 97657-97670. doi:10.18632/oncotarget.18280
  28. Paul, A., & Paul, S. (2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci (Landmark Ed), 19, 605-618. Retrieved from http://dx.doi.org/
  29. Petrucelli, N., Daly, M., & Pal, T. (2016). BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer (Text) (Publication no. https://www.ncbi.nlm.nih.gov/books/NBK1247/).  Retrieved 2016/12/15, from University of Washington, Seattle https://www.ncbi.nlm.nih.gov/pubmed/
  30. Roy, R., Chun, J., & Powell, S. N. (2012). BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer, 12(1), 68-78. doi:10.1038/nrc3181
  31. Singer, C. F., Balmaña, J., Bürki, N., Delaloge, S., Filieri, M. E., Gerdes, A.-M., . . . Evans, D. G. (2019). Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer&#x2014;an European consensus statement and expert recommendations. European Journal of Cancer, 106, 54-60. doi:10.1016/j.ejca.2018.10.007
  32. Tew, W. P., Lacchetti, C., Ellis, A., Maxian, K., Banerjee, S., Bookman, M., . . . Kohn, E. C. (2020). PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. J Clin Oncol, 38(30), 3468-3493. doi:10.1200/jco.20.01924
  33. Tomao, F., Musacchio, L., Di Mauro, F., Boccia, S. M., Di Donato, V., Giancotti, A., . . . Benedetti Panici, P. (2019). Is BRCA mutational status a predictor of platinum-based chemotherapy related hematologic toxicity in high-grade serous ovarian cancer patients? Gynecol Oncol, 154(1), 138-143. doi:10.1016/j.ygyno.2019.04.009
  34. USPSTF. (2019, August 20). BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. Retrieved from https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing
  35. Walsh, C. S. (2015). Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol, 137(2), 343-350. doi:10.1016/j.ygyno.2015.02.017
  36. Yoo, J., Lee, G. D., Kim, J. H., Lee, S. N., Chae, H., Han, E., . . . Kim, M. (2020). Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome. Ann Lab Med, 40(2), 148-154. doi:10.3343/alm.2020.40.2.148
  37. Yoshida, K., & Miki, Y. (2004). Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci, 95(11), 866-871.

Coding Section 

Code 

Number

Description

CPT      

81162         

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81163

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81164

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81165

BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81166

BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81167

BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81212

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants

 

81215

BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant

 

81216

BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81217

BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant

 

96040

Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family 

 

S0265

Genetic counseling, under physician supervision, each 15 minutes

 

0172U 

Oncology (solid tumor as indicated by the label), somatic mutation analysis of BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) and analysis of homologous recombination deficiency pathways, DNA, formalin-fixed paraffin-embedded tissue, algorithm quantifying tumor genomic instability score
Proprietary test: myChoice® CDx
Lab/Manufacturer: Myriad Genetics Laboratories, Inc
 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2018 Forward     

05/04/2021 

Corrected formatting. No other changes made. 

04/07/2021 

Annual revivew, multiple policy criteria rewritten for clarity and specificity. Also updating decription, rationale and references. 

2/4/2021 

Corrected Formatting. No change to policy intent 

01/21/2021 

Interim review, updating description, policy, references and rationale. Adding "exocrine" to clarify pancreatic cancer updating policy language related to PARP inhibitor coverage. 

10/01/2020 

Interim review adding code 0172U to coding section. No other changes. 

06/29/2020 

Corrected typos in policy section. No, change to policy intent 

04/16/2020 

Annual review, updating criteria based on NCCN guidelines related to age ranges for testing. NO other changes made. 

07/15/2019 

Updating coding section. No other changes made. 

04/02/2019 

Annual review with reformatting and revision of medical policy criteria, also reformatting description, rationale and references. 

01/08/2019 

Interim review, updating policy verbiage for clarity, also updating coding. 

12/19/2018

Updating with 2019 codes.  

11/27/2018 

Updated policy with 2019 coding. No other changes made. 

08/15/2018 

Corrected formatting issues. 

06/26/2018 

Updated coding section. Removed codes  81432, 81433, 81479, 81519, 81520, 81521, 83950, 84233, 84234, 88360. 88361, S3854. No other changes made

05/10/2018 

Interim review, expanding medical necessity criteria related to first or second degree relatives who meet the criteria in #2. Adding investigational statement for testing family members for a variant of unknown significance. 

04/30/2018 

Updated Next Review Date. No change to policy intent 

02/14/2018 

Interim review to add clarifying language to medical necessity criteria #4, also removing criteria #6 as it is addressed in a separate policy. No other changes made. 

12/7/2017 

Updating policy with 2018 coding. No other changes. 

07/31/2017 

Correcting formatting error in coverage criteria 3 last bullet points.

05/04/2017 

Corrected a typo in the Rationale section. No other changes.

04/18/2017 

Annual review, extensive revision of policy verbiage for clarity and updated coverage. Updating coding. 

01/05/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

04/26/2016 

Interim review to update verbiage related to testing with a history of pancreatic and prostate cancers. 

02/04/2016 

Updating criteria for patients without cancer or without history of cancer criteria for 1st or 2nd degree relatives to add specificity and clarity of information. 

01/06/2016 

Annual review, no change to policy intent. Updated background, description, regulatory status, rationale, references and coding. 

02/03/2015 

Annual review, CHEK2 eliminated from policy and added coding.

 01/15/2014

Annual review, updated ratonale, reference, guidelines. Added related policy. Update policy verbiage to include " including those with a family history of pancreatic cancer" to the investigational statement to mirror BCA change.


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