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Can population-based DNA sequencing identify those at risk for hereditary cancers?

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It is well documented that many BRCA mutation carriers are missed using current family history-based screening approaches. As a result, experts are beginning to call for population-based BRCA genetic testing—an organized effort to screen all women like we do for breast and cervical cancer.  A recent study looked at whether a population-based genetic testing approach would better identify mutation carriers compared with current practice. (11/17/18)



Study findings                                                        In-Depth Review of Research

This study is about                                                 Limitations

What does this mean for me?                               References                

Questions to ask your health care provider        Other resources                  



This study is about:

Whether population-based screening for BRCA1 and BRCA2 mutations may  identify substantially more patients who are at high risk for hereditary cancers than the current practice of using personal and family cancer history alone.

Why is this study important?

Identifying more patients who carry mutations in BRCA1 or BRCA2 provides an opportunity for improved cancer prevention, early detection, and access to new targeted therapies.

Study findings: 

Adult participants were recruited from January 2014 to March 2016 through the Geisinger MvCode Community Health Initiative in Pennsylvania and New Jersey. Over 50,000 participants enrolled and consented to complete DNA sequencing of BRCA1 and BRCA2.  

Of the 50,726 patients who underwent DNA sequencing, over 99% did not have a mutation. A BRCA1 or BRCA mutation was found in 0.5% (about 1 in 200) people tested.

Almost half of the  89 BRCA1 or BRCA2 mutation carriers who had not had  prior testing and for whom comprehensive personal and family medical histories were available did not meet NCCN  guidelines for clinical testing. These people would have been missed using standard recommendations for genetic counseling and testing.

These results are consistent with previous studies that showed that about 1 in 500 to 1 in 300 people in the general population will carry a BRCA1 or BRCA2 mutation. Like other studies, the results confirm that about half of all people with a BRCA1 or BRCA2 mutation do not have a strong family history of cancer.

What does this mean for me?

The National Comprehensive Cancer Network (NCCN) is a nonprofit network of leading cancer centers that publishes guidelines for genetic counseling and testing for BRCA. Current NCCN guidelines for mutations in BRCA1 and BRCA2 are based on personal and family history of cancer(s). However, these guidelines are not always applied correctly; nor do they always identify all BRCA mutation carriers.

The guidelines are based in part on having a noticeable family history of breast or ovarian cancer. This is harder to observe when families are small or if the BRCA mutation is inherited from the father's side of the family or if there is lack of information (e.g. with adoptees).

This new research adds to other studies that have shown that current ways of identifying BRCA1 and BRCA2 mutation carriers are insufficient. Population-based genetic testing for inherited BRCA mutations may be a better way to identify high-risk patients and provide to them opportunities to reduce their risk of cancer. For more information on cancer risk management for mutation carriers click here.

At the recent 2018 Joining FORCEs Conference, renowned scientist Dr. Mary-Claire King, who discovered the BRCA1 gene, told attendees, “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention.” While Dr. King and others have been calling for population-based genetic testing for BRCA mutations, this is a bold challenge that demands careful consideration.

Questions to ask your health care provider

  • Do I meet criteria for genetic counseling and testing for BRCA1, BRCA2, or other high-risk cancer genes?
  • If I do not meet criteria for genetic testing for high-risk cancer genes, what are the risks and benefits of genetic counseling and testing for me?
  • Will my insurance pay for testing? If not, what are the costs for the test?


Study background:

Clinical testing for BRCA mutations has been available for over 20 years. In the United States, between 1 in 300-500 are estimated to have an inherited BRCA mutation. This translates to between 250,000 and 415,000 women for whom breast and ovarian cancer is both highly likely and potentially preventable.  However, the majority of these women do not know that they have a BRCA mutation.

The U.S. Preventative Services Task Force recommends testing only in at-risk populations. The guidelines are based in part on having a noticeable family history of breast or ovarian cancer. This is harder to observe when families are small or if the BRCA mutation is inherited from the father's side of the family or if there is lack of family medical information (e.g. with adoptees).

Some experts are concerned that guidelines are too narrow. A recent, eye-opening study out of Israel, for example, found that 50% of all women with a BRCA mutation had no history of breast or ovarian cancer. Some experts, including Dr. Mary-Claire King, now advocate voluntary genetic testing for all women after the age of 30.

Researchers of this study wanted to know:

Is population-based genetic testing a better way to identify BRCA mutation carriers than current practice?

Study design:

This was a study of 50,726 adults who had exome sequencing from January 2014 to March 2016 as voluntary participants of the DiscovEHR cohort identified through the Giesinger MyCode Community Health Initiative in Pennsylvania.  (Conducting sequencing on the portions of genes that encode proteins (exons) helps researchers to identify genetic mutations that influence disease.) Comparisons were made between clinical data from electronic health records and clinical visits.

Study findings:

Among the 50,726 patients who underwent sequencing:

  • 50,459 (99.5% of patients tested) did not have a disease-causing mutation in BRCA1 or BRCA2.
  • 267 (0.5% of patients tested) had inherited BRCA mutations.
    • Among these patients:
      • 219 (82.%) had no prior clinical testing
      • 95 (35.6%) had a mutation in BRCA1; 172 (64.4%) had a mutation in BRCA2.
      • 148 (55.4%) were women and 119 (44.6%) were men.
      • Cancer was diagnosed in 56 (20.9%) of all 267 BRCA mutation carriers.

Twenty BRCA mutation carriers died before they received their results and 3 died after return of results (before June 30, 2017). Among the 23 deaths, the cause of death was determined to be a BRCA-associated cancer in 9 (39.1%) people. Cause of death was unrelated to BRCA in 11 (47.8%) and indeterminate in 3 (13%).  Compared to deceased cases, 45 (18.4%) of living BRCA mutation carriers had a personal history of a BRCA-associated cancer.

Among the 148 women with BRCA mutations:

  • 31 (20.9%) had a personal history of breast cancer as did 1,544 (5.2%) of 29,880 noncarriers.
  • 15 (10.1%) had a personal history of ovarian cancer as did to 195 (0.6%) of 29,880 noncarriers.

Among 89 BRCA1 or BRCA2 mutation carriers without prior testing but with comprehensive personal and family medical histories:

  • 44 (49.4%) did not meet published guidelines for clinical testing.


Age was one limitation of this study. Participants were generally older than the health system’s patient population. More importantly, this study was skewed toward those patients who received regular health care, thereby increasing the opportunity to enroll in the biobank research. The higher incidence of breast cancer in the biobank population was also likely a reflection of age and frequency of care. 


Inherited BRCA mutations predispose women to extremely high risks of breast and ovarian cancer, but these risks can be significantly lowered. For women with mutations in BRCA1 or BRCA2, surgical intervention,  particularly risk-reducing salpingo-oophorectomy, reduces risk of both ovarian and breast cancer and reduces overall mortality. However, many women with mutations in these genes are identified as carriers only after their first cancer diagnosis because their family history of cancer was not sufficient to suggest genetic testing.

Although this study and others support genetic screening in healthy patients, we still do not have a perfect, all inclusive way to do that effectively.  Minimally, patients must have good genetic counseling about the potential benefits and drawbacks of genetic testing.

Posted 11/17/18


Manickam K, Buchanan AH, Schwartz MLB,  et al., "Exome Sequencing–Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants."  JAMA Netw Open. 2018. 1(5):e182140.

King, M-C, Levy-Lahad E, and Lahad A. "Population-Based Screening for BRCA1 and BRCA2."  JAMA. 2014. 312(11):1091-1092.

Gabai-Kapara E, Lahad A, Kaufman B, et al. "Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2." Proc Natl Acad Sci U S A. 2014. 111(39):14205-10.

Related Information and Resources

FORCE Information: Genetic Testing for Hereditary Cancer

FORCE XRAYS category:  Genetic Testing

FORCE Webinars category:  Risk Assessment, Genetic Counseling and Genetic Testing

The Promise and Peril of Panel Genetic Testing for Inherited Cancer Susceptibility (March 24, 2015)

The "New" Genetic Testing: What You Need to Know (November 18, 2013)

Genetics and Risk Basics (June 2012)

Cancer Basics (March 28, 2012)

Genetics 101 (March 10, 2011)

GINA Update: The Newly Enacted Federal Ban on Genetic Discrimination and What It Means for You (April 13, 2010)

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