BlueCross BlueShield of Tennessee Medical Policy Manual

BRCA1, BRCA2 and PALB2 Testing for Breast, Ovarian and Other Cancers


Hereditary breast and ovarian cancer (HBOC) syndrome describes the familial cancer syndromes related to genetic variants. Families with HBOC syndrome have an increased susceptibility to 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, as well as other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and/or laryngeal cancer.

Highly penetrant genes variants associated with breast cancer include BRCA1, BRCA2, PALB2, TP53, PTEN, STK11, and CDH1.  Clinical management guidelines associated with highly penetrant variants from the National Comprehensive Cancer Network address appropriate genetic testing guidance, cancer surveillance strategies such as self-exam, mammogram, and MRI as well as risk-reducing interventions such as prophylactic mastectomy.

Recent studies determined the estimated cumulative risk of breast cancer for female carriers of PALB2 mutations to be 14% by age 50 and 35% by age 70, representing a significant increase over the general population. Individuals with PALB2 mutations with a significant family history of breast cancer were at even higher risk; 27% and 58% at age 50 and 70, respectively.

First degree relatives are parents, siblings or children, second degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings, third degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins.

Note: BRCA 1 and BRCA 2 have both common (small rearrangements) and uncommon (large rearrangements) variations in DNA segments that disrupt function.  Newer technologies and products allow for analysis of additional rare large genomic rearrangements [e.g. BRACAnalysis® Large Rearrangement Test (BART™)]. There is an MCG Guideline that address this testing specifically (BRCA - Uncommon Duplication or Deletion Variants ACG: A-0638) as well as MCG’s for other highly penetrant gene variants TP53, PTEN, STK11, and CDH1.





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 have access to an FDA Clinical Laboratory Improvement Amendments (CLIA) licensed laboratory.


American College of Radiology (2010) Breast cancer screening with imaging: recommendations from the society of breast imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. Journal of the American College of Radiology; 7:18-27.

Antoniou, A.C., Casadei, S., Heikkinen, T., Barrowdale, D., Pylkäs, K., Roberts, J., et al. (2014). Breast-cancer risk in families with mutations in PALB2. The New England Journal of Medicine, 371 (6), 497-506. (Level 3 evidence)

BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2016). Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer (2.04.126). Retrieved August 1, 2017 from BlueWeb. (74 articles and/or guidelines reviewed)

BlueCross BlueShield Association. Medical Policy Reference Manual. (11:2016). Genetic testing for hereditary breast and/or ovarian cancer syndrome (BRCA1/BRCA2) (2.04.02). Retrieved July 19, 2017 from BlueWeb. (76 articles and/or guidelines reviewed)

Couch, F., Hart, S., Sharma, P., Toland, A., Wang, X., Miron, P., Olson, J., et al., (2014) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. Journal of Clinical Oncology, 33 (4), 304-311. (Level 2 evidence)

Fernandes, P., Saam, J., Peterson, J., Hughes, E., Kaldate, R., et al. (2014). Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer. Cancer, 120 (7), 963-967. (Level 2 evidence)

Haanpää, M., Pylkäs, K., Moilanen, J., and Winqvis, R. (2013) Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families . BMC Medical Genetics, 14 (82). (Level 2 evidence)

Janatova, M., Kleibl, Z., Stribrna, J., Panczak, A., Vesela, K., Zimovjanova, M., et al. (2013). The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. Cancer Epidemiology, Biomarkers & Prevention, 22 (12), 2323-2332. (Level 3 evidence)

Kraus, C., Hoyer, J., Vasileiou, G., Wunderle, M., Lux, M., Fasching, P., et al. (2017, January) Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. International Journal of Cancer, 140 (1), 95-102. Abstract retrieved July 10, 2017 from PubMed database.

National Comprehensive Cancer Network. (2016, December). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: breast and ovarian Version 2.2017. Retrieved July 10, 2017 from:

National Government Services, Inc. (2017, August) Local Coverage Determination (LCD): Molecular pathology procedures (L35000). Retrieved August 2, 2017 from

National Government Services, Inc. (2017, August) Local Coverage Determination (LCD): MolDX: BRCA1 and BRCA2 genetic testing (L36813). Retrieved August 2, 2017 from

National Institute for Health and Care Excellence (NICE). (June, 2013 last update March 2017). Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. Retrieved July 10, 2017 from: 

Snyder, C., Metcalfe, K., Sopik, V., Royer, R., Zhang, S., et al. (2015). Prevalence of PALB2 mutations in the Creighton University breast cancer family register. Breast Cancer Research and Treatment, 150 (3), 637-641. Abstract retrieved April 16, 2015 from PubMed database.

Sokolenko, A., Preobrazhenskaya, E., Aleksakhina, S., Iyevleva, A., Mitiushkina, N., et al. (2015). Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients. Cancer Letters, 359 (2), 259-261. Abstract retrieved April 16, 2015 from PubMed database.

Southey, M., Teo, Z., Dowty, J., Odefrey, F., Park, D., Tischkowitz, M., et al., (2010) A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Research, 12 (R109). (Level 3 evidence)

Tung, N., Lin, N., Kidd, J., Allen, B., Singh, N., Wenstrup, R., et al., (2016, May) Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. Journal of Clinical Oncology, 34 (13) 1460-1468. (Level 3 evidence)

U.S. Preventive Services Task Force (USPSTF). (February, 2014). Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Retrieved April 14, 2015 from the National Guideline Clearinghouse (NGC:010191).

Vietri, M., Caliendo, G.,Schiano, C., Casamassimi, A., Molinari, A., Napoli, C., et al. (2015). Analysis of PALB2 in a cohort of Italian breast cancer patients: identification of a novel PALB2 truncating mutation. Familial Cancer. Abstract retrieved on June 16, 2015 from PubMed database.

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Report. (2014, August). PALB2-associated hereditary breast cancer. Retrieved April 14, 2015 from (44 articles and/or guidelines reviewed)

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Report. (2012, November, last update search 2014, December). Panexia Test for hereditary pancreatic breast cancer. Retrieved April 14, 2015 from (40 articles and/or guidelines reviewed)  




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