Patients of childbearing age should be informed that Fanconi anemia is associated with having two copies of a PALB2 pathogenic variant (one from each parent). The chance of having a child with Fanconi anemia is 25% for every pregnancy if both parents have a pathogenic variant.

Prevention and Early Detection

The American College of Medical Genetics and Genomics strongly suggests basing patient management for a pathogenic PALB2 on family and personal history. This requires construction of a three-generation pedigree of both paternal and maternal history and a patient’s own history of malignancy.

Management of breast cancer risk includes screening and consideration of risk-reduction surgery. Screening can include:

• Annual mammography starting by age 30, with consideration of breast magnetic resonance imaging (MRI) alternating every six months with mammography
• Clinical breast exam every 6–12 months, starting at age 25
• Monthly breast self-examination starting at age 18, with prompt evaluation of any change

Men should also be instructed on the importance of prompt evaluation of any breast changes and have an annual clinical breast exam.

Women with a pathogenic PALB2 variant who are diagnosed with breast cancer and those with a strong family history of breast cancer may want to discuss their considerations for risk-reducing mastectomies as well as options for breast reconstruction.

Tamoxifen and raloxifene, medications used to treat breast cancer, have been shown to reduce the risk for certain types of breast cancer by up to 50% in women with associated pathogenic variants. Individuals can consider using the medications for five years.

Because risk for ovarian cancer is increased, women with a pathogenic variant can consider transvaginal ultrasound screening of the ovaries and a CA-125 blood test every six months, starting at approximately age 30. Some women consider surgery to remove the ovaries and fallopian tubes at age 40–45 or when childbearing is complete, especially for those with a family history of ovarian cancer.

In men and women with a family history of pancreatic cancer, consider annual pancreatic screening starting at age 45 or 10 years prior to the age of the earliest pancreatic cancer diagnosis in the family. Recommended initial screening is MRI/magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), fasting blood glucose, and HbA1c; alternate annual MRI/MRCP and EUS with annual fasting blood glucose and HbA1c thereafter.

Treatment Implications

Breast and pancreatic tumors in patients with germline pathogenic PALB2 variants have homologous recombination repair deficiency (HRD), which makes them more vulnerable to platinum-based chemotherapy. HRD also increases sensitivity to poly(ADP)-ribose polymerases (PARP), which led to the clinical development of PARP inhibitors.