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Study: Can population-based DNA sequencing find more people at risk for hereditary cancers?

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This study is about:

Whether population-based screening for and 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 or 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 sequencing of and .  

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

Almost half of the  89 or 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 or mutation. Like other studies, the results confirm that about half of all people with a or 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 . Current NCCN guidelines for mutations in and are based on personal and family history of cancer(s). However, these guidelines are not always applied correctly; nor do they always identify all mutation carriers.

The guidelines are based in part on having a noticeable family history of breast or ovarian cancer. These guidelines are likely to miss people with mutations:

  • who come from small families 
  • when the mutation is inherited from the father's side of the family
  • 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 and mutation carriers are insufficient. Population-based genetic testing for inherited 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 2018 Joining FORCEs Conference, renowned scientist Dr. Mary-Claire King, who discovered the 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 mutations, this is a bold challenge that demands careful consideration.

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Posted (6/21/19)


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 and ."  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 and ." Proc Natl Acad Sci U S A. 2014. 111(39):14205-10.


FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

Women over age 30

This article is also relevant for:


men with breast cancer

people with breast cancer

healthy people with average cancer risk

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Study background:

Clinical testing for mutations has been available for over 20 years. In the United States, between 1 in 300-500 are estimated to have an inherited 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 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 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 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 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 or .
  • 267 (0.5% of patients tested) had inherited 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 .
      • 148 (55.4%) were women and 119 (44.6%) were men.
      • Cancer was diagnosed in 56 (20.9%) of all 267 mutation carriers.

Twenty 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 in 11 (47.8%) and indeterminate in 3 (13%).  Compared to deceased cases, 45 (18.4%) of living mutation carriers had a personal history of a BRCA-associated cancer.

Among the 148 women with 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 or 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 mutations predispose women to extremely high risks of breast and ovarian cancer, but these risks can be significantly lowered. For women with mutations in or , 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

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Expert Guidelines
Expert Guidelines

NCCN guidelines recommend genetic counseling and testing for people without cancer who have the following family history:

  • A relative who has tested positive for an in a gene that increases cancer risk.
  • One or more first- or second-degree relatives with breast cancer and any of the following:
    • diagnosed at age 45 or younger
    • two separate breast cancers, with the first diagnosis at age 50 or younger
    • male breast cancer
  • One or more first- or second-degree relatives with:
    • colorectal cancer before age 50
    • endometrial cancer before age 50
    • ovarian, , primary peritoneal cancer
    • rare or childhood cancers
  • One or more first-degree relatives with:
    • or high-grade cancer
    • pancreatic cancer
  • Two or more relatives on the same side of the family diagnosed with any combination of the following at any age:
    • breast cancer
    • pancreatic cancer
    • cancer
    • melanoma
    • sarcoma
    • adrenal cancer
    • brain tumors
    • leukemia
    • endometrial cancer
    • thyroid cancer
    • kidney cancer
    • diffuse gastric cancer
    • colon cancer

Updated: 12/04/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Do I meet criteria for genetic counseling and testing for , , 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?

Open Clinical Trials
Open Clinical Trials

The following clinical trials include genetic counseling and testing. 

Other genetic counseling or testing studies may be found here.


Updated: 02/29/2024

Find Experts
Find Experts

The following resources can help you locate a genetics expert near you or via telehealth.

Finding genetics experts

  • The National Society of Genetic Counselors website has a search tool for finding a genetic counselor by specialty and location or via telehealth. 
  • InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference. 
  • Gene-Screen is a third-party genetic counseling group that can help educate, support and order testing for patients and their families. 
  • JScreen is a national program from Emory University that provides low-cost at-home genetic counseling and testing with financial assistance available.
  • Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone. 
  • The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors. 

Related experts

Genetics clinics

Other ways to find experts

Updated: 07/21/2023

Who covered this study?

Yale Daily News

Most with cancer risk don’t know it, study finds This article rates 4.0 out of 5 stars

Medical Express

Genomic screening can ID undetected BRCA1/2 cancer risk This article rates 2.0 out of 5 stars

How we rated the media

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