ACS Research Highlights

Study of High-Risk Genes May Inform Breast Cancer Screening

For the first time, researchers recently looked at the prevalence of known breast-cancer predisposition genes in a population that included women without cancer.

The Challenge

Not all types of cancer are hereditary, but certain types of breast cancer are caused by an inherited gene mutation. About 7 to 10% of women with breast cancer have a pathogenic variant in a cancer predisposition gene. (See blue box at bottom for lay-friendly explanations about inheriting cancer risks.)

These statistics are based on populations with a high risk for developing breast cancer, which includes women with more than one close female relative (mother, sister, daughter) with breast cancer or who was diagnosed with breast cancer before age 50.

But studies to learn about women with breast cancer who don’t have one of these characteristics have been limited in size. And there haven’t been many studies to estimate the prevalence and risk of breast cancer associated with breast cancer-predisposition genes in the general population.

More research on the prevalence of these genes in the general population could offer valuable knowledge about the causes of cancer and could improve the prevention, diagnosis, and treatment of cancer.

The Research

Several American Cancer Society researchers, including current staff Alpa Patel, PhD,James Hodge, PhD, and Brian Carter, MPH, along with grantees, contribute to the work of the United States-based Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, which conducts population- and family-based studies of breast cancer.

Their studies are the first large studies to use data from general population studies, including the American Cancer Society’s Cancer Prevention Studies II (CPS-II) and 3 (CPS-3), rather than data from families.

The Cancer Prevention Studies have played a role in identifying or validating every known common genetic variant for breast, prostate, and pancreatic cancers. This was the first large study to look at the prevalence of breast-cancer predisposition genes in the general population.”

Alpa Patel, PhD

Senior Vice President, Population Science

American Cancer Society


The researchers recently published a study of the general population and previously identified breast-cancer predisposition genes. The researchers looked at studied data about 28 cancer predisposition genes among 32,2347 women with breast cancer and 32,544 women without breast cancer. Their goal was to learn how common, or prevalent, pathogenic variants in breast cancer predisposition genes are in women with and without breast cancer.  

Their results included finding pathogenic variants in:

  • 12 established cancer predisposition genes in 5% of women with breast cancer and almost 2% without cancer.
  • The genes BARD1, RAD51C, and RAD51D were only associated with an increased risk of developing estrogen receptor-negative (ER-) breast cancer.
  • The genes BRCA1, BRCA2, and PALB2 were linked with all breast cancers, but they were more strongly linked ER- breast cancers.
  • The genes ATM, CDH1, and CHEK2 were associated with an increased risk of developing estrogen receptor-positive (ER+) breast cancer.
  • 16 breast cancer predisposition genes were not associated with an increased risk of breast cancer

Why It Matters

Currently, recommendations are not clear about which women with breast cancer should receive genetic counseling and testing and which genes to look for. There's increasing discussion about screening for pathogenic variants in the BRCA1 and BRCA2 genes in women without breast cancer.

It’s important that women who have variants in these genes talk to their doctor about their cancer risk and the best screening plan for them. They may need to be screened more often or have different tests, such as 3D mammograms or MRIs.

The results from this study provide refined estimates about the prevalence of pathogenic variants among women with breast cancer and in the overall population, which adds to the base of evidence that helps to inform recommendations for women in the general population, including:

  • Genetic testing. For instance, recommendations could become more solid and could broaden to include other genetic mutations.
  • Cancer screening. For example, if a woman has one of more these mutations, she could be in the high-risk category. Current ACS screening recommendations for women at high risk include getting a breast MRI and mammogram every year, typically starting at age 30.
  • Other risk-management strategies (like risk assessment and counseling) for women with pathogenic variants in cancer-predisposition genes.

Previous ACS researchers who participated in this study: Sue Gapstur, PhD, Mia Gaudet, PhD, and Eric Jacobs, PhD

Current and previous ACS research grantees who also participated in this study:Fergus J. Couch, PhD, (ACS Grant Term: 7/1/2004 to 6/30/2009), Julie R Palmer, ScD, (ACS grant term: 1/1/2018 to 12/31/2021), and Jeffrey N. Weitzel, MD, (ACS grant term: 1/1/2010 to 12/31/2013 and 7/1/2010 to 6/30/2016)

Inheriting Cancer Risks: Some Basic Terms

Permanent changes in the DNA sequence of a gene are called gene mutations. Some scientists think that “gene variant” is a more accurate term because changes in DNA do not always lead to disease. Sometimes they’re used as synonyms.

Genetic variants can have a large or small effect on the likelihood of developing a particular disease. The term “pathogenic” refers to something that causes a disease. When genetic variants lead to disease, they’re called pathogenic variants, or pathogenic mutations.

Genes that are vulnerable to cancer-causing variants or changes are called cancer-predisposition genes. In some cases, a cancer-predisposition gene is inherited, or passed along from generation to generation. Several dozen cancer-predisposition genes have been identified, and about 5 to 10% of all cancers result directly from those that are inherited from a parent.

For example, BRCA1 and BRCA2 are inherited cancer predisposition genes. Mutations on these genes increase the risk for developing certain cancers.

The type of gene changes that get passed from parents to a child are called “germline variations.” Since the BRCA1 and BRCA2 mutations are passed down by parents, they’re an example of what are considered germline pathogenic variations.

Peoplewho inherit certain changed genes that make them more likely to develop cancer are said to have a genetic predisposition or a genetic susceptibility to a cancer or certain types of cancer. Sometimes this is referred to as having a family cancer syndrome. But having this doesn’t mean that person will develop cancer. And if they do develop cancer, it may not be caused by the inherited genetic mutation.

The term penetrance is used to describe how many people carrying a mutation or cancer predisposition gene will eventually develop cancer. If everyone who inherits a mutation develops cancer, that mutation is said to have complete penetrance. If some people don’t, it’s incomplete or reduced penetrance. If most people with an inherited mutation develop cancer, that mutation has high penetrance. For example,pathogenic variations on the BRCA1 and BRCA2 genes are high-penetrance gene mutations. Other gene mutations are in categories considered to be moderate- or low-penetrance.