PALB2-associated hereditary cancer

What Does It Mean to Test Positive for a PALB2 Mutation?

Mutations in PALB2 are associated with an increased risk to develop breast and pancreatic cancer. However, it is important to understand that the risk of cancer is not 100%, which means that not everybody with a PALB2 mutation will develop cancer.

What Are the Cancer Risks Associated with a PALB2 Mutation?

PALB2 mutations are associated with an increased risk of breast cancer and pancreatic cancer. Women with PALB2 mutations have up to a 33 to 58% lifetime risk of developing breast cancer. For men, the breast cancer risk is eight times greater than the general population's risk of 0.1%, yet it is still rare. Pancreatic cancer is also associated with mutations in PALB2; however, the exact risk of pancreatic cancer for PALB2 mtuation carriers is not yet known.

Cancer Type Cancer Risk Average Age of Onset General Population Risk
Female Breast 33-58% 40 to 49 Years 12.4%
Male Breast Increased Unknown <1%
Pancreatic Increased Unknown 1.6%

For women, breast-cancer risks have been shown to vary significantly based on age and family history of breast cancer. Cancer risks may be higher for individuals with a strong family history of breast cancer.

Age No Family History Mother with Early-Onset Breast Cancer Two or More First-Degree Relatives
30 <1% <1% 1%
40 3-6% 5-10% 6-11%
50 9-20% 16-31% 21-33%
60 19-35% 31-51% 38-54%
70 26-46% 41-63% 50-66%
80 34-55% 50-72% 59-75%

Data adapted from Antoniou AC, et al. (2014)

PALB2 mutations have been reported in patients with other types of cancers, such as ovarian cancer; however, more research is needed to determine the associated cancer types and risks. While screening and management guidelines for female breast cancer and pancreatic cancer exist for those who test positive for a PALB2 mutation, there are currently no screening or management recommendations for other possible cancers.

What Cancer-Screening or Risk-Reducing Options Are Available?

The most important aspect of management of an individual with a PALB2 mutation is increased cancer screening, to allow the earliest possible detection of any tumors. Management guidelines for PALB2 mutation carriers are evolving and are often individualized based on family history.

For Women

  • Mammography, with consideration of 3D mammogram (tomosynthesis) and breast MRI, is recommended once a year beginning at age 30 or earlier, based on family history.
  • Bilateral mastectomy (surgical removal of both breasts) may be considered.

For Men and Women

  • Pancreatic cancer screening guidelines are not well-established, and additional research is needed to determine their effectiveness. However, the Cancer of the Pancreas Screening Consortium (CAPS) recommends that PALB2 mutation carriers with a family history of pancreatic cancer in a first-degree relative (e.g., a parent, sibling, or child), consider screening beginning at age 50. Screening may include evaluation of biomarkers, MRI of the abdomen, and endoscopy studies.

What Is the Chance That Family Members of PALB2 Mutation Carriers Have the Same Mutation?

PALB2 mutations are passed down in a family. This means that family members of PALB2 mutation carriers may have the same mutation and may also be at increased risk to develop cancer. For this reason, it is important for PALB2 mutation carriers to discuss genetic test results with family members.

  • Close blood relatives of PALB2 mutation carriers, such as parents, siblings, and children, have a 50% chance of having the same mutation.
  • Distant relatives, such as aunts, uncles, grandparents, and cousins, also have a chance of having the same PALB2 mutation.
  • A physician or a genetic counselor can help mutation carriers determine whether the mutation was more likely to have been inherited from the maternal or paternal side of the family. In general, the mutation will only be inherited from one side of the family, and it is more likely to be inherited from the side of the family that has a history of pancreatic or breast cancer.

Genetic testing of family members can help determine which family members may have an increased risk for cancer and may benefit from the screening and/or risk-reduction options discussed above. Family members who test negative for a known familial PALB2 mutation likely have the same risk for cancer as the general population and can follow the general population's screening guidelines.

What Else Should PALB2 Mutation Carriers Know?

In rare instances, an individual may inherit two mutations in PALB2, one from each parent. This has the potential to result in a rare condition called Fanconi anemia. Most individuals with Fanconi anemia develop symptoms in childhood and may have both physical and developmental disabilities. For individuals who test positive for PALB2, it may be appropriate to consider carrier screening for PALB2 mutations in a spouse or partner.

Mutation carriers who are interested in options to prevent passing their mutation to future children may wish to consider preimplantation genetic diagnosis (PGD). PGD is a procedure that involves in vitro fertilization (IVF) and can determine if an embryo carries the genetic mutation present in a family. Determining which embryos carry the family mutation may allow a mutation carrier to prevent the condition from being passed to future children. The decision to undergo PGD is personal. Mutation carriers and their family members can talk with a healthcare provider to learn more about their reproductive options.