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Gene mutation

Updated: Feb 6, 2021

High risk gene mutations

  • PALB2: The PALB2 (partner and localizer of BRCA2) gene provides instructions to make a protein that works with the BRCA2 protein to repair damaged DNA and stop tumor growth. Research suggests that women with a PALB2 mutation have a 14% risk of developing breast cancer by age 50, but that risk jumps to 35% by age 70. And for those with a family history, the risk of breast cancer by age 70 is 58%.

  • In comparison, women with an abnormal BRCA1 gene have a 50% to 70% risk of developing breast cancer by age 70. Women with an abnormal BRCA2 gene have a 40% to 60% risk of developing breast cancer by age 70.

  • PTEN: The PTEN gene helps regulate cell growth. An abnormal PTEN gene causes Cowden syndrome, a rare disorder in which people have a higher risk of both benign (not cancer) and cancerous breast tumors, as well as growths in the digestive tract, thyroid, uterus, and ovaries. The lifetime breast cancer risk for women with a PTEN mutation is estimated at 25% to 50%, although some studies have reported a higher risk, at 77% to 85%. The average age at diagnosis is 38 to 50 years.

  • TP53: The TP53 gene provides instructions to the body for making a protein that stops tumor growth. Inheriting an abnormal TP53 gene causes Li-Fraumeni syndrome, a disorder in which people develop soft tissue cancers at a young age. People with this rare syndrome have a higher-than-average-risk of breast cancer and several other cancers, including leukemia, brain tumors, and sarcomas (cancer of the bones or connective tissue). A study by the National Cancer Institute suggested women with Li-Fraumeni syndrome have a 54% risk of developing breast cancer by age 70. Also, women with this syndrome tend to develop breast cancer at earlier ages and may be more likely to have HER2-positive cancers. The risk of getting any type of cancer in women with a TP53 mutation is up to nearly 100%. In men, it is up to 73%. This gender difference is mostly due to the high breast cancer risk in women.

Moderate to high risk gene mutations

  • ATM: The ATM gene helps repair damaged DNA. DNA carries genetic information in cells. Inheriting two abnormal copies of this gene causes ataxia-telangiectasia, a rare disease that affects brain development. Inheriting one abnormal ATM gene has been linked to an increased rate of breast cancer and pancreatic cancer in some families. That’s because the abnormal gene stops the cells from repairing damaged DNA. Research suggests that ATM mutation carriers have a 33% to 38% lifetime risk of developing breast cancer (by age 80). However, for those with a certain type of mutation affecting a specific location on the ATM gene, the lifetime risk is estimated to be 69%.

  • CDH1: The CDH1 gene makes a protein that helps cells bind together to form tissue. An abnormal CDH1 gene increases the risk of a rare type of stomach cancer at an early age. The lifetime risk for this stomach cancer is up to 83%.

Moderate risk gene mutations

  • CHEK2: The CHEK2 gene provides instructions for making a protein that stops tumor growth. An abnormal CHEK2 gene can at least double the lifetime risk of breast cancer. It can also increase colorectal and prostate cancer risk. For women with CHEK2 mutations and a family history of breast cancer, the lifetime risk of breast cancer is estimated to range from 28% to 37%. However, the risk may be higher depending on the number of family members affected by breast cancer.

  • NBN: The NBN gene controls production of a protein called nibrin, which helps repair DNA damage in cells. An abnormal NBN gene causes Nijmegen breakage syndrome, a condition that results in slow growth in infancy and early childhood. People with Nijmegen breakage syndrome are shorter than average, have a higher risk of several types of cancer (including breast cancer), and have many other health problems. Research is limited, but studies suggest that people with certain NBN mutations may have a two- to three-times greater lifetime risk of developing breast cancer.

  • NF1: An NF1 mutation causes a condition called neurofibromatosis type 1, which increases the risk of central nervous system cancers and a specific type of cancer that grows in the wall of the stomach or intestines, called gastrointestinal stromal tumors. The lifetime risk of cancer overall is nearly 60%. Some studies have suggested that women with an NF1 mutation are at higher risk of developing breast cancer, especially before age 50.

  • STK11: The STK11 gene helps regulate cell growth. An abnormal STK11 gene causes Peutz-Jeghers syndrome, a rare disorder in which people tend to develop a type of polyp, called a hamartomatous polyp, mostly in the small intestine but also in the stomach and colon. In addition to gastrointestinal cancers, people with Peutz-Jeghers syndrome are also at higher risk of breast cancer, lung cancer, and ovarian tumors. People with Peutz-Jeghers syndrome may also develop freckling around the eyes, nose, and mouth, as well as inside the mouth. Genetic mutations with uncertain breast cancer risk

Other gene mutations are sometimes found in families with a strong history of cancer. Mutations in the genes listed below may or may not cause an increased risk of breast cancer. Further research is needed to tell what the increased breast cancer risk is, if any.

  • BARD1: BARD1 (BRCA1 Associated Ring Domain 1) is a gene that works with BRCA1 to repair damaged DNA. Some studies have suggested that BARD1 mutations can increase breast cancer risk.

  • BRIP1: The BRIP1 gene also works to repair DNA. Right now, a BRIP1 mutation is associated with a higher lifetime risk of ovarian cancer. There is not enough evidence to link it with increased breast cancer risk.

  • MLH1, MSH2, MSH6, PMS2, EPCAM: All of these are called mismatch repair genes, and they work to repair any mistakes that occur when DNA copies itself. Inherited mutations in these genes lead to a condition known as Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC). People with Lynch syndrome are at higher risk of colorectal cancer and other cancers, including endometrial and ovarian cancer. Some research suggests that the MLH1 and MSH2 mutations may be linked to an increased risk of breast cancer.

  • RAD51C and RAD51D: These genes are involved in repairing DNA damage. Both have been linked to a small increase in the lifetime risk of ovarian cancer. They have not been linked to elevated breast cancer risk.

Inheriting two abnormal copies of the BRCA2, BRIP1, NBN, PALB2, or RAD51C genes causes the disease Fanconi anemia, which suppresses bone marrow function and leads to very low levels of red blood cells, white blood cells, and platelets. People with Fanconi anemia also have a higher risk of several other types of cancer, including kidney cancer and brain cancer.

Genetic testing

There are genetic tests available to determine if someone has inherited an abnormal BRCA1 or BRCA2 gene. A genetic counselor also may order testing for mutations in the ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 and/or MLH1, MSH2, MSH6, PMS2, EPCAM genes. They can be tested for individually or as part of a larger gene panel that includes BRCA1 and BRCA2. Decisions about what tests to perform are based on your personal or family history of breast cancer and other cancers.


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