Genetics and risk of breast cancer

Most breast cancers are not inherited, and only a small number of people have an increased risk of developing breast cancer because they have a significant or strong family history.

Around 5-10% of breast cancers are thought to be hereditary, that is, caused by an abnormality in a gene passed from a mother or father to their child. If one of your close family members such as your mother, father, sister or daughter have been diagnosed with breast cancer, you may be concerned about your risk of developing breast cancer.

There are several genes in which mutations (gene abnormalities or faults) may be involved in the development of breast cancer. These may include rare to very rare high-risk gene mutations, such as those in BRCA1 and BRCA2, PALB2, TP53, PTEN, CDH1 and STK11 and some rare moderate-risk gene mutations such as ATM, CHEK2, RAD51C and RAD51D.

Genes

A gene is a basic unit of heredity. Each person has genes that carry information that determines the features or characteristics passed on to you (inherited) from your parents. Each human cell has about 25,000 genes. Genes are what make up our chromosomes. We have two copies of each gene, one from our mother and one from our father. Each gene helps make proteins in the body cells. These proteins help your body work properly and stay healthy.

It is normal to have variations in the gene code - this is what makes us unique, within our family and within our ethnicity. If a variation occurs in the gene code and it alters the function of the gene, these changes are called pathogenic variants or mutations.

Cancer begins when genes in cells become abnormal and the cells starts to grow and divide in an uncontrolled manner. For example, some cancer-causing gene changes increase the production of a protein that makes cells grow.

Genetic changes that increase cancer risk can be inherited from our parents. The genetic changes that relate to hereditary breast cancer are often in genes that normally work to stop abnormal cell growth.

Cancer-causing genetic changes can also be acquired during one’s lifetime, as a result errors occur as cells divide. This can be from exposure to cancer causing substances that damage DNA, such as alcohol, certain chemicals in tobacco smoke and radiation from ultraviolet rays from the sun.

Family history and genetic factors

Some people with a family history of breast cancer may have inherited a faulty gene that increases their risk of breast cancer. We inherit a set of genes from each of our parents, and sometimes a gene mutation in one copy of a gene prevents it from working properly, leading to an increased risk of breast cancer. Therefore, a family history on your father’s side is just as important as a family history on your mother’s side.

A significant or strong family history is likely if two or more close relatives are diagnosed with breast cancer at a younger age particularly if this breast cancer is a triple negative breast cancer, male breast cancer, the person is of Ashkenazi Jewish descent or there is a history of breast and ovarian cancer in the one family.

Read more about Breast cancer in the family. 

Inherited gene mutations associated with an increased risk of breast cancer

BRCA1 and BRCA2 gene mutations

The most common inherited gene mutations that increase the risk of breast cancer are in the genes called BRCA1 and BRCA2 (i.e. BRCA stands for BReast CAncer). The BRCA1 and BRCA2 genes usually protect us from developing breast cancer. However, inheriting a pathogenic variant (gene mutation) in one of these genes increases the risk of developing cancer.

Women who have a BRCA1 or BRCA2 mutation (or both) can have up to a 72 per cent risk of being diagnosed with breast cancer during their lifetime. Men who have a BRCA2 mutation can have a higher risk of breast cancer than men who do not. It is about 8 per cent by the time they are 80 years of age. Triple negative breast cancer is more common with BRCA1 and young women with BRCA2 related breast cancer.

Both men and women can inherit, carry and pass on a gene mutation that increases the risk of breast cancer. If one family member has a genetic mutation linked to breast cancer it does not mean that all family members will have it. It is important to remember genetic mutations are uncommon.

Other genes 

Other inherited gene mutations that have been associated with some increase in breast cancer risk.

High risk gene mutations 

PALB2: After BRCA1 and BRCA2, PALB2 is currently the third most common high risk breast cancer gene. The PALB2 gene works in partnership with the BRCA2 gene to repair damage and help prevent breast cancer from developing. A mutation in the PALB2 gene increases the risk of developing breast cancer. An estimated 53% per cent of women with a mutated PALB2 gene will develop breast cancer by the age of 80. The PALB2 mutation is associated with an increased risk for triple negative breast cancer in younger women as well as male breast cancer. PALB2 is also associated with an increased risk for ovarian cancer in women and in some families a risk for pancreatic cancer. 

TP53: The TP53 gene provides instructions to the body for making a protein that stops tumour growth. Inheriting a faulty TP53 gene causes Li-Fraumeni syndrome, a disorder in which people develop soft tissue cancers at a young age. Women with this syndrome are more likely to develop breast cancer at a younger age, and it is more likely to be HER2-positive breast cancer. This gene abnormality results in an increased risk for many different types of cancer including cancers in children. It is extremely rare. 

Moderate risk gene mutations

CHEK2: The CHEK2 gene provides instructions for making a protein to stop cancer growth. In men, it makes male breast cancer 10 times more likely to occur. Breast cancer risk can be low to moderate in some families but moderate to high in others. The CHEK2 mutation is associated with an increased risk for DCIS as well as breast cancer, with the risks for either being between 17 and 30%. This risk can be estimated more accurately in a family cancer centre (specialist genetic clinic).

ATM: The ATM gene helps repair damaged DNA. Inheriting an abnormal ATM gene has been linked to an increase in breast cancer or DCIS and pancreatic cancer in some families. This happens because the abnormal ATM gene stops the cells from repairing DNA that is damaged. Breast cancer risk can vary from low to moderate depending on your family history. This risk can be estimated more accurately in a family cancer centre (specialist genetic clinic).

CDH1: The CDH1 gene makes a protein that helps cells bind together to form tissues in the body. Women with an abnormal CDH1 gene have a higher risk of invasive lobular breast cancer. Lobular breast cancer is the second most common type of breast cancer. The risk for breast cancer is approximately 40% during a lifetime for lobular breast cancer. Most breast cancers are ductal breast cancer- CDH1 does not increase the risk for ductal breast cancer.

RAD51C: The RAD51C gene interacts with the BRCA genes. An abnormality in this gene can be associated with a moderately increased risk for breast cancer (about double the general population risk), but triple negative breast cancer is more commonly associated with this gene abnormality. This gene is also associated with an increased risk for ovarian cancer.

NF1: An NF1 gene mutation causes a condition called neurofibromatosis type 1, which increases the risk of cancers in the central nervous system. This is an extremely rare condition. Women with an NF1 mutation have a moderately higher risk of developing breast cancer (18% lifetime risk).

PTEN: The PTEN gene helps regulate cell growth by controlling the rate of cell division. It also causes damaged cells to self-destruct before they become cancerous. An abnormal PTEN gene causes Cowden syndrome, a rare condition in which people have a higher risk of both non-cancerous (benign) and cancerous breast tumours as well as cancer in the bowel, thyroid, uterus and ovaries. The risk of breast cancer is unclear but at least moderately increased.

STK11: The STK11 gene helps control cell growth. STK11 gene mutations cause Peutz-Jeghers syndrome (PJS) (non-cancerous growths/polyps in the gastrointestinal tract). An abnormal STK11 gene is associated with gastrointestinal cancers and a moderately increased risk of breast cancer. This is an extremely rare condition.

Gene mutations with uncertain breast cancer risk

Mutations in the genes below may or may not cause an increased risk of breast cancer, and further research is needed to understand their impact:

• BARD1
• BRIP1
• MLH1, MSH2, MSH6, PMS2, EPCAM (Lynch Syndrome)
• RAD51D.

These genes are involved in repairing damage to DNA. These genes are associated with an increased risk for other cancers, such as ovarian, bowel or endometrial cancer, but some studies suggest mutations in these genes can also increase the risk of breast cancer.

Genetic testing

Genetic testing is the testing of a person’s genes and is usually offered when someone is at high risk of having inherited a faulty gene, based on a strong family history of cancer or the age at which they are diagnosed, or the type of breast cancer they have been diagnosed with (triple negative breast cancer).

Not all pathology laboratories do genetic testing. The process involves taking blood or saliva from the person who has a specific cancer. If the faulty gene is found, testing may be offered to other family members who have no signs of cancer.

A panel genetic test looks for changes in many genes in one test and are grouped into genes that are all associated with a higher risk of developing certain kinds of cancer, like breast cancer.

Genetic testing can be ordered by either a specialist family cancer clinics (e.g. genetics specialist) or a breast cancer specialist. The results of genetic testing might change the treatments a breast specialist recommends and, therefore, it might be offered by your specialist early after your diagnosis of breast cancer.

Genetic testing results are given back to you after the test is complete. For most people having gene testing, no mutation will be found and the gene test report will say “no pathogenic variant identified”. In this case, there would not be a need for other family members to think about a genetic test. Cancer risk is likely to be low to moderate for you and your family.

If a genetic mutation is found, this is known as a “pathogenic variant”. In other words, the variation (e.g. mutation) in the gene stops the gene from working correctly. If a pathogenic variant is found, other family members may be eligible for gene testing (whether they have a cancer history or not). As most breast cancer genes are not related to a risk of cancer in childhood, gene testing is only offered to adults. If you are found to have inherited a gene mutation, your breast cancer risk will be higher than for women who do not have a gene mutation.

If a genetic variant (alteration) is found, but current research does not know whether the alteration causes the gene to stop working, this is known as a variant of uncertain significance. This can be unsettling, but it is important to remember that most variants of uncertain significance will not alter the function of the gene. Genetic testing is not available for family members. It is more common to see a variant of uncertain significance if your ethnicity is not Caucasian.