Other Hereditary Breast and/or Ovarian Cancer and the ATM, BRIP1, CHEK2, PALB2, RAD51C and RAD51D genes

Other genes associated with Hereditary Breast and Ovarian Cancer syndrome

The BRCA1 and BRCA2 genes don't work alone to protect us from breast, ovarian, prostate and pancreatic cancer. The genes on this page are also important.

There is ongoing research into these genes to determine the cancer risk and guidelines are likely to change over time.

Like the BRCA1 and BRCA2 genes, BRIP1, PALB2 and RAD51C can cause Fanconi anaemia. Fanconi anaemia occurs if a baby inherits two mutations in the same gene, one from each parent (biallelic inheritance). These children are usually born with deformities and/or developmental issues and the bone marrow doesn't work properly. If a baby inherits 2 mutations in ATM another severe disease, Ataxia Telangiectasia, develops. Carrier testing of a partner may be considered before having children.

The ATM gene

The ATM gene works with the BRCA genes to repair DNA damage. A woman who inherits an ATM mutation is at moderate risk for breast cancer (15 to 30% lifetime risk). However, one particular spot in the gene is very important. A mutation here, written ATM c.7271T>G, is associated with a high risk (30 to 80% lifetime) of breast cancer for women, which is similar to carrying a BRCA2 gene mutation. Read more about the ATM gene.

The BRIP1 gene

BRIP1 stands for BRCA1 Interacting Protein C-Terminal Helicase 1. It works with BRCA1 to fix DNA damage.

Mutations in BRIP1 are associated with increased risk of ovarian cancer. The risk is still being determined, but is likely 4% to 12% over a lifetime (which is significantly less than for BRCA1, where the risk is 20 to 60% lifetime).

Most guidelines recommend removing the ovaries and fallopian tubes around age 55, when the risk starts to rise, and rarely before menopause.

Perhaps surprisingly, BRIP1 has not been shown to increase breast cancer risk. Also, some BRCA-related cancer treatments, such as PARP inhibitors, don't seem to work in individuals with BRIP1 mutations.

The CHEK2 gene

CHEK2, like its name suggests, provides a Check Point that cells have to pass before they can divide. Its full name is Checkpoint Kinase 2. It give the BRCA genes the time they need to fix DNA damage.

CHEK2 is called a moderate risk gene. If the gene is knocked out completely (a "truncating" mutation), the lifetime risk of breast cancer for women is 15 to 30% while a change that may affect the function of CHEK2 (a "missense" mutation) is likely to associated with a smaller risk of 10 to 20%. One specific mutation, known as the CHEK2 1100delC mutation, is found in 1 to 2% of Europeans.

Most guidelines recommend women start breast screening at age 40 and consider annual screening.

Some research has suggested a link between CHEK2 mutations and prostate cancer and even colon cancer. Screening in this case is based on the family history, starting earlier than the population-based guidelines if there is a history these cancers in close relatives.

The PALB2 gene

PALB2 stands for Partner and Localiser of BRCA2. It works with the BRCA genes to fix DNA mistakes.

A woman who carries a PALB2 mutation is at a high risk of breast cancer over her lifetime (30 to 60%, with some effect of family history). Some women would elect to remove the breast tissue (bilateral mastectomies) at this level of risk. The residual risk of breast cancer is then very low, <2% (which is significantly lower than the population based risk of 10%).

Other women elect to pursue increased breast screening. This screening is the same as for BRCA2 mutation carriers: annual mammograms and breast MRI starting at age 30. Medicare pays for the breast MRI's, if they are ordered by a Specialist, between the ages of 30 and 50.

Breast cancer risk for men with PALB2 mutations is increased but is still low (~1% lifetime) and no screening is required

Recent research has shown that ovarian cancer risk is also increased in women who carry PALB2 mutations. The risk is 2 to 10% over a woman's lifetime (For BRCA2, the risk is 10 to 20% lifetime). Ovarian cancer screening with blood tests or ultrasounds doesn't work . It doesn't save lives or reduce treatments and has actually be associated with harm. Instead, a laparoscopic (keyhole) surgery to remove the ovaries and fallopian tubes (a risk reducing salpingo-oophorectomy) is strongly recommended at age 50.

Like BRCA2, PALB2 increases pancreatic cancer risk. In this case it is likely a 2 to 3% chance over a lifetime. Not smoking is very important as it double this risk.

If you carry a PALB2 gene mutation, you may consider being involved in the research study run by the PABL2 Interest Group, an international consortium of scientists and clinicians working to better understand the PALB2 gene.

The RAD51C and RAD51D genes

The RAD51C and RAD51D also work with the BRCA genes to fix DNA mistakes.

Both RAD51C and RAD51D mutations increase ovarian cancer risk. The lifetime risk of ovarian cancer is 5 to 20% over a lifetime. The risk in young women is small (<1%) but climbs from age 50. To reduce this risk, the ovaries and fallopian tubes should be removed after age 45 and by age 50.

RAD51C and RAD51D are not believed to have a big impact on breast cancer risk. Women are advised to start breast screening with mammograms every 2 years from age 50 or annually if there is a family history of breast cancer.

Other genes

Most of the genes listed above are involved in DNA repair. A very important gene, TP53, is involved in Quality Insurance. Other genes increase breast cancer risk because they encourage cell growth. Many of these genes go with other outward signs or symptoms (a phenotype). In particular they may be associated with unusual skin changes. Follow the link to read more about them on their individual pages.

Does this sound like you or your family? Has an ATM, BRIP1, CHEK2, PALB2, RAD51C or RAD51D mutation been detected in a blood relative? Make an appointment with Dr Hilda High at Sydney Cancer Genetics. It is a confidential opportunity to discuss your personal and family history of cancer and genetic testing can be organised, if needed.