Awareness of the various genetic mutations that can lead to breast cancer is necessary in understanding the risk factors for the disease, particularly when it comes to hereditary forms. While mutations in the BRCA1 and BRCA2 genes are now well-publicized, there are other, lesser-known genetic mutations which can significantly increase the likelihood of developing breast cancer as well. Understanding these genetic risks allows individuals to make informed decisions about their health, from preventive measures to early detection strategies. Here, we discuss the lesser-known genetic mutations that can also impact the risk of developing breast cancer.
TP53 (tumour Protein 53)
Li-Fraumeni syndrome (LFS) is linked to mutations in the TP53 gene, called a tumour suppressor gene, which normally acts as a safeguard to stop cells from growing and dividing too quickly. When this gene is mutated, the protein it produces becomes inactive, causing tumor cells to lose their protection against genetic changes. As a result, people with LFS have a very high risk—up to 90%—of developing one or more types of cancer by age 60, with many facing cancer before they turn 40. For women with LFS, breast cancer is the most common type, and many are diagnosed before the age of 40. Breast cancers in women with a TP53 mutation are more likely to be hormone receptor-positive (HR+) and/or HER2-positive.
PTEN (phosphatase and TENsin homolog)
The PTEN gene is another important tumor suppressor, and mutations in this gene are most commonly linked to Cowden syndrome. This condition increases the risk of developing benign tumors, but also raises the likelihood of certain cancers, including breast cancer. PTEN mutations are not only associated with breast cancer but also with endometrial, thyroid, kidney, and colorectal cancers. PTEN mutations are often found in more aggressive subtypes of breast cancer, and loss of PTEN function has been linked to poorer responses to trastuzumab (Herceptin), a drug used to treat HER2-positive breast cancer.
CDH1 (cadherin 1)
The CDH1 gene is linked to an increased risk of two types of cancer: diffuse gastric cancer and invasive lobular carcinoma (ILC), a form of breast cancer. The CDH1 gene provides instructions for making a protein called E-cadherin, which is crucial for holding cells together. When this gene is mutated, it disrupts cell bonding, which can lead to the development of cancer. Around 6% of new cases of ILC are linked to genetic mutations, including those in the CDH1 gene. Changes in this gene have been linked to a 55% lifetime risk of developing ILC. Genetic testing for CDH1 mutations is especially recommended for people with early-onset ILC (under age 45), bilateral ILC (both breasts affected, especially in those over 70), or a strong family history of ILC. Provincial genetic testing criteria may not reflect these recommendations, so we encourage a discussion with your doctor to explore your eligibility.
STK11 (serine/threonine kinase 11)
STK11 is another important tumor suppressor gene, and mutations in this gene are linked to Peutz-Jeghers syndrome (PJS). PJS can show early signs during childhood, such as darker skin spots around the mouth, lips, fingers, and toes, and some people may also develop freckling inside the mouth. One of the main features of PJS is the growth of hamartomatous polyps, which are non-cancerous lumps in the gastrointestinal tract. While most cancers related to PJS occur in the digestive system, individuals with STK11 gene mutations are also at a higher risk of developing breast cancer, especially as they age.
PALB2 (partner and localizer of BRCA2)
PALB2 is a tumour suppressor gene that works closely with BRCA2 to help prevent healthy cells from becoming cancerous. PALB2 mutations are associated with a high risk of breast cancer and moderately high risk of ovarian and pancreatic cancer. Subtypes associated with the PALB2 mutation are most often estrogen receptor-positive (ER+) but have also been linked to triple negative as well. People with this mutation are also more often diagnosed at a younger age.
CHEK2 (checkpoint kinase 2)
The CHEK2 gene helps repair damaged DNA and control cell growth. People with a CHEK2 mutation are more likely to develop breast cancer, often before age 50, and are more likely to develop invasive ductal carcinoma (IDC) or ductal carcinoma in situ than other types of breast cancer. Some studies suggest that individuals with CHEK2 mutations could be at an increased risk of breast cancer recurrence over a 10-year period.
ATM (ataxia telangiectasia-mutated)
Mutations in the ATM gene cause Ataxia Telangiectasia, a rare inherited disorder that affects the nervous system and increases the risk of breast cancer. ATM-mutated breast cancers are more commonly ER+, and may be more aggressive and harder to treat.
Genetic testing is the only way to positively confirm the presence of a genetic mutation associated with cancer. Hereditary cancer risk assessment is a process used to estimate the likelihood of inheriting mutations in cancer-related genes, based on both personal and family medical histories. This assessment includes genetic counseling, testing, and managing individuals who may be at risk, helping them make informed decisions about cancer surveillance, preventive surgeries, and the use of medications or other treatments to lower cancer risk.
A proper hereditary cancer risk assessment is essential for understanding both personal and family risks for breast cancer and other cancers. To help guide these decisions, individuals are encouraged to discuss key questions with their doctors, and they can refer to our Hereditary Breast Cancer Syndrome factsheet for more information on genetic testing and personalized cancer screening and care.
Receive updates by email 
