Genetic Risk, Assessment, Application, and Recommendations in Breast Cancer


Women being screened for breast cancer using mammography, or who are undergoing diagnostic procedures, are often asked if they have a known history of breast or other cancers in a family member — on both maternal and paternal sides – and also if they have particular ancestry. This information becomes integrated into their family history and contributes to risk assessment related to breast cancer. A woman whose family has a significant history of breast, ovarian, prostate, and/or pancreatic cancer in addition to her personal diagnosis of breast cancer, may represent a good candidate for genetic testing and counseling, especially if hereditary cancer mutations have not already been found in the person’s relative(s).

All cancers develop as a result of genetic changes or mutations. Hereditary, or germline, mutations, can be inherited from other family members and also passed along to children.1 Germline mutations are relatively rare (<20% of cancers are thought to be due to inherited mutations) and can be found in any cell of the body, not just tumor cells. The most well-known hereditary mutations in breast cancer are BRCA1 and BRCA2. Since these germline mutations may be detected prior to the clinical diagnosis of a cancer, assessment of these mutations may be applied to primary prevention of breast cancer or altering the surveillance approach in order to detect a cancer at the earliest time possible.

Acquired mutations are much more common, and occur as a result of other genetic changes or exposures, e.g. tobacco, hormones, chemicals, adiposity, etc.2, and are found in tumor tissues. Thus, assessment of acquired mutations may help identify targets and treatments that might apply to prognosis or prediction of therapeutic effectiveness.

The National Comprehensive Cancer Network (NCCN)3, along with many other groups and agencies4,5,6,7, has established guidelines for genetic/familial high-risk assessment in multiple tumor types. For breast cancer, the NCCN currently recommends testing individuals that meet the following criteria:

  • With blood relatives who have known/likely pathogenic variants
  • Diagnosed with breast cancer at age <45 years or diagnosed age 45-50 years with either unknown or limited family history
  • Diagnosed at any age with second breast primary OR if they are of Ashkenazi Jewish ancestry
  • Diagnosed with triple-negative (ER-, PR-, HER2-) breast cancer at <60 years

In 2019, based on reports that documented patients who did not meet NCCN guidelines were found with similar mutation rates as those who did,8,9 the American Society of Breast Surgeons (ASBS) established consensus guidelines10 that recommend ALL patients with a personal history of breast cancer be considered for genetic testing for BRCA1, BRCA2, PALB2, and other genes. In addition, the ASBS recommended that patients who previously had genetic testing before 2014 be considered for repeat testing since current testing includes better technology as well as inclusion of other important genes, such as PALB2, that were not available earlier. The ASBS recommendations run counter to the U.S. Preventive Services Task Force recommendations, that indicate women with a, “personal or family history of breast, ovarian, tubal, or peritoneal cancer or an ancestry associated with BRCA1/2 gene mutation” should undergo genetic testing (Evidence Grade of B), whereas the USPSTF recommends against routine genetic counseling, testing or risk assessment in any women who do not meet these guidelines (Evidence Grade of D).11

A recent study12 looked at all women diagnosed at the Mayo Clinic from 2000-201 (N=3907) and were tested for germline pathogenic variants in nine breast cancer predisposition genes: BRCA1 and BRCA2, as well as PALB2, CDH1, CHEK2, NF1, PTEN, TP53 and ATM. Based on the NCCN guidelines, less than half of the sample (47.9%) met criteria for testing. However, of those women who did not meet NCCN criteria, 13.1% were found to have mutations in BRCA1 or BRCA2, and 29.9% were found to have variants in the nine-gene panel. However, no evaluation of cost-effectiveness of this broader-based testing was done.

Although the clinical and testing recommendations may differ, all of these groups are clear that breast cancer risk assessment is an important component of breast cancer diagnosis and care. In addition, if an institution/practice takes on genetic testing, they must have resources in place to provide such vital services as pre- and post-testing genetic counseling (which can be physicians, nurses, genetic counselors, or other professionals with the needed expertise), appropriate referral, support services for families who may be affected, and resources for preventive and/or surveillance if the testing demonstrates pathogenic variants.13 Lastly, not all insurance payors cover the costs of genetic testing14; thus, providers should check with the payor to understand what services will (or will not) be covered.


1. Mahdavi M, Nassiri M, Kooshyar MM, Vakili-Azghandi M, Avan A, Sandry R, Pillai S, Lam AK, Gopalan V. Hereditary breast cancer; Genetic penetrance and current status with BRCA. J Cell Physiol. 2019 May;234(5):5741-5750. doi:10.1002/jcp.27464. Epub 2018 Dec 14. Review. PubMed PMID: 30552672.

2. Zhang Y, Xiong S, Liu B, Pant V, Celii F, Chau G, Elizondo-Fraire AC, Yang P, You MJ, El-Naggar AK, Navin NE, Lozano G. Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases. Nat Commun. 2018 Sep27;9(1):3953. doi: 10.1038/s41467-018-06146-9. PubMed PMID: 30262850; PubMed Central PMCID: PMC6160420.


Accessed 3/11/2020.

4. Committee on Practice Bulletins—Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol. 2017 Sep;130(3):e110-e126. doi:10.1097/AOG.0000000000002296. PubMed PMID: 28832484.

5. Berliner, J.L., Fay, A.M., Cummings, S.A. et al. NSGC Practice Guideline: Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer. J Genet Counsel 22, 155—163 (2013).

6. Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015 Jan;136(1):3-7. doi: 10.1016/j.ygyno.2014.09.009. Epub 2014 Sep 17. Erratum in: Gynecol Oncol.2015 Sep;138(3):765. PubMed PMID: 25238946.

7. ASCO Guidelines on Assessing and Managing your Patient’s Hereditary Cancer Risks. Accessed 3/9/2020.

8. Beitsch PD, Whitworth PW, Hughes K, Patel R, Rosen B, Compagnoni G, Baron P, Simmons R, Smith LA, Grady I, Kinney M, Coomer C, Barbosa K, Holmes DR, Brown E, Gold L, Clark P, Riley L, Lyons S, Ruiz A, Kahn S, MacDonald H, Curcio L, Hardwick MK, Yang S, Esplin ED, Nussbaum RL. Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol. 2019 Feb 20;37(6):453-460. doi: 10.1200/JCO.18.01631. Epub 2018 Dec 7. PubMed PMID:30526229; PubMed Central PMCID: PMC6380523.

9. Yang, S., Axilbund, J.E., O’Leary, E. et al. Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark. Ann Surg Oncol 25, 2925—2931 (2018).

10. Manahan, E.R., Kuerer, H.M., Sebastian, M. et al. Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol 26, 3025—3031 (2019).

11. U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Recommendation Statement. Am Fam Physician. 2015 Jan 15;91(2): Online. PubMed PMID: 25591222.

12. Yadav S, Hu C, Hart SN, Boddicker N, Polley EC, Na J, Gnanaolivu R, Lee KY, Lindstrom T, Armasu S, Fitz-Gibbon P, Ghosh K, Stan DL, Pruthi S, Neal L, Sandhu N, Rhodes DJ, Klassen C, Peethambaram PP, Haddad TC, Olson JE, Hoskin TL, Goetz MP, Domchek SM, Boughey JC, Ruddy KJ, Couch FJ. Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer. J Clin Oncol. 2020 Mar 3: JCO1902190. doi:10.1200/JCO.19.02190. [Epub ahead of print] PubMed PMID: 32125938.

13. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol.2003 Jun 15;21(12):2397-406. Epub 2003 Apr 11. PubMed PMID: 12692171.

14. Amendola LM, Hart MR, Bennett RL, Horike-Pyne M, Dorschner M, Shirts B, Jarvik GP. Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests. J Genet Couns. 2019 Dec;28(6):1208-1213. doi: 10.1002/jgc4.1155. Epub 2019 Jul 17. PubMed PMID: 31317629; PubMed Central PMCID: PMC6901727.

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