How Much Do Mutations in Genes Other Than BRCA1 and BRCA2 Increase Breast and Ovarian Cancer Risk?

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About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.

Genes are short segments of DNA (deoxyribonucleic acid) found in chromosomes. DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.

Think of your genes as an instruction manual for cell growth and function. Abnormalities in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. This is like having an instruction manual in which all the copies have the same typographical error.

We’ve known for many years that mutations in the BRCA1 and BRCA2 genes are linked to a higher risk of breast cancer. Women who have a BRCA1 or BRCA2 mutation (or both) can have up to an 80% risk of being diagnosed with breast cancer during their lifetimes. Now we also know that other gene mutations are linked to breast cancer, including mutations in the PALB2 and CHEK2 genes. But it’s been unclear how common these other mutations are, as well as how much they increase the risk of breast cancer.

A study has found that four non-BRCA genes up the risk of breast cancer between 2 and more than 5 times higher than average.

The research was published online on Aug. 16, 2018 by the journal JAMA Oncology. Read “Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing.”

Comparing mutations in diagnosed and non-diagnosed people

The study included 11,416 people diagnosed with breast cancer, ovarian cancer, or both who were recommended to have genetic testing between 2014 and 2015. None of these people in the study were related.

Of the 9,639 people diagnosed with breast cancer:

  • 3,960 people (41.1%) were diagnosed at age 45 or younger
  • 123 people (1.3%) were men
  • 1,321 people (13.7%) had cancer in both breasts or were diagnosed with more than one breast cancer
  • 641 people (6.6%) were diagnosed with another cancer in addition to breast or ovarian cancer
  • 8,152 people (84.6%) had a family history of cancer

Of the 2,015 women diagnosed with ovarian cancer:

  • 445 (21.7%) were diagnosed at age 45 or younger
  • 1,670 (81.4%) had a family history of cancer

The researchers also found that 2,060 of the people diagnosed with breast or ovarian cancer in the study had earlier BRCA1/BRCA2 mutation testing. Nearly all of them -- 2,034 (98.7%) -- had received negative results.

The study also included 3,988 people who were recommended to have genetic testing because they had been diagnosed with a non-cancerous disease, such as cystic fibrosis. None of the people who had genetic testing for a non-cancerous disease were related and none of them had been diagnosed with cancer.

Whole-exome sequencing offers more information

All the people in the study had whole-exome sequencing. Whole-exome sequencing figures out the precise order of all the DNA in all the expressed genes in the genome. A genome is an organism’s complete set of DNA, including all its genes. In humans, the genome contains more than 3 million DNA base pairs. Whole-exome sequencing offers much more detailed information than a typical genetic test.

The researchers then used special software to analyze differences in the exomes of the people who had been diagnosed with cancer and the people who hadn’t been diagnosed with cancer.

The researchers found four genes in which mutations were linked to higher breast cancer risk:

  • PALB2: The PALB2 gene provides instructions to make a protein that works with the BRCA2 protein to repair damaged DNA and stop tumor growth. This study found that women with a PALB2 mutation had a breast cancer risk that was 5.5 times higher than average. Men with a PALB2 mutation had a breast cancer risk that was 22.7 times higher than average.
  • ATM: The ATM gene helps repair damaged DNA. In women, this study found an ATM mutation was linked to a risk of breast cancer that was nearly 3 times higher than average.
  • CHEK2: The CHEK2 gene provides instructions for making a protein that stops tumor growth. In this study, women with a CHEK2 mutation had a breast cancer risk that was about twice as high as average risk. Men with a CHEK2 mutation had a breast cancer risk that was 1.66 times higher than average.
  • MSH6: The MSH6 gene provides instructions for making a protein that helps repair DNA damage. This study found that women with a MSH6 mutation had a breast cancer risk that was 2.59 times higher than average.

The researchers also found four genes in which mutations were linked to higher ovarian cancer risk, two of which were also linked to a higher risk of breast cancer:

  • RAD51C: The RAD51C gene repairs DNA damage. RAD51C mutations have been linked to a higher risk of ovarian cancer in earlier studies. The researchers in this study were not able to calculate how much a RAD51C mutation increased ovarian cancer risk because not enough people in the study had this mutation.
  • TP53: The TP53 gene provides instructions to the body for making a protein that stops tumor growth. Women with a TP53 mutation had a risk of ovarian cancer that was 18.5 times higher than average.
  • ATM: Women with an ATM mutation had an ovarian cancer risk that was 2.85 times higher than average.
  • MSH6: Women with an MSH6 mutation had an ovarian cancer risk that was 4.16 times higher than average.

In this study, the researchers did not find a link between higher breast cancer risk and mutations in the CDKN2A, BRIP1, RAD51C, RAD51D, MSH2, or PMS2 genes. This contradicts findings from earlier studies, which found a link between mutations in those genes and higher breast cancer risk.

The researchers said that they hope their study helps determine which genes should be included in standardized genetic testing for breast and ovarian cancer.

Does genetic testing make sense for you?

If you have a strong family history of breast or ovarian cancer, you may want to talk to your doctor or a licensed certified genetic counselor about your family history and ask if having a multigene panel test makes sense for you. You also may be considering ordering an at-home genetic test, such as Color or 23andMe. No matter which genetic test you have, it is very important to know exactly which genes and mutations the test is analyzing. A licensed certified genetic counselor or your doctor can help you understand the test and accurately interpret the results.

For more information on genetic testing, including types of genetic tests and how results are reported, visit the Breastcancer.org Genetic Testing pages.

For more information on genes and genetic mutations linked to breast cancer, as well as all the risk-lowering steps you can take if you have a genetic mutation, visit the Breast Cancer Risk Factors: Genetics page in the Breastcancer.org Lower Your Risk section.

If you've tested positive for a genetic mutation and would like to discuss how this affects your risk with others, join the Breastcancer.org Discussion Board forum Positive Genetic Test Results.


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