The presence of a pathogenic variant in the PALB2 gene (Partner and Localizer of BRCA2) significantly increases a person’s lifetime risk for developing certain cancers. This gene is classified as a tumor suppressor gene, playing a role in maintaining the stability of the body’s genetic material. Identifying a PALB2 mutation does not guarantee a cancer diagnosis, but it provides an opportunity for proactive health management through enhanced surveillance and risk-reducing strategies.
The Function of the PALB2 Gene
The normal PALB2 gene provides instructions for making a protein that is a component of the cell’s DNA repair machinery. Specifically, it is part of the homologous recombination repair (HRR) pathway, which fixes double-strand breaks in DNA. These breaks are a form of DNA damage that occur naturally or are caused by environmental factors.
The PALB2 protein links the BRCA1 and BRCA2 proteins together into a complex required for effective DNA repair. It acts as a bridge, facilitating the function of BRCA2 and helping to localize it to the site of the DNA damage. When a pathogenic mutation occurs in PALB2, the resulting protein is non-functional or absent, which disrupts this repair complex.
This failure to repair damaged DNA causes genomic instability, meaning the cell accumulates errors in its genetic code as it divides. Cells with accumulated errors are more likely to grow uncontrollably, which is the defining characteristic of cancer, leading to an elevated cancer risk.
Cancer Risks Associated with PALB2
A pathogenic PALB2 mutation raises the lifetime risk for several types of cancer, primarily breast cancer. For women with a PALB2 mutation, the estimated lifetime risk of developing breast cancer ranges from 35% to 53%, compared to a general population risk of about 12.5%. This risk may be higher, up to 58%, for women who also have a strong family history of the disease.
The risk for male breast cancer is also elevated, estimated to be around 0.9% to 1% over a lifetime. This is significantly higher than the general male population risk of about 0.1%. The mutation is also associated with an increased risk of developing a second (contralateral) breast cancer in women previously diagnosed with the disease.
The mutation confers an increased risk for pancreatic cancer, with lifetime risk estimates generally ranging between 2% and 5%. This is approximately two to three times the risk of the general population. The risk for ovarian cancer is less pronounced than for breast cancer, with estimates suggesting a lifetime risk of about 3% to 5%. This risk may be strongly influenced by family history of ovarian cancer. The association with prostate cancer is still under investigation, suggesting a possible increased risk.
Genetic Testing and Inheritance
PALB2 mutations are inherited in an autosomal dominant pattern, meaning a person needs to inherit one copy of the altered gene from either parent to have an increased cancer risk. If a parent carries a PALB2 pathogenic variant, there is a 50% chance of passing that variant on to each child, regardless of the parent’s sex.
Genetic testing for a PALB2 mutation is generally recommended for individuals with a personal history of associated cancers, particularly if diagnosed at a young age, or those with a strong family history of breast, ovarian, or pancreatic cancer. Testing involves a blood or saliva sample analyzed in a specialized lab. Results usually take several weeks to process.
Genetic counseling is essential both before and after testing. Before testing, a genetic counselor helps the individual understand the potential results and the implications for family members. After a positive result, the counselor provides a detailed, personalized assessment of cancer risks and guidance on medical management options.
Personalized Medical Surveillance
Identifying a PALB2 mutation allows for enhanced medical surveillance aimed at early cancer detection and risk reduction. For female carriers, breast cancer screening protocols are intensified, often starting at a younger age than for the general population. Recommended surveillance typically involves annual breast magnetic resonance imaging (MRI) and annual mammograms, often staggered throughout the year to provide overlapping coverage.
These screening measures often begin around age 30, or sometimes earlier depending on the youngest age of breast cancer diagnosis in the family. Risk-reducing surgery, such as a prophylactic mastectomy, can lower breast cancer risk by approximately 90% and is a decision made through discussion with a healthcare provider. While routine ovarian cancer screening is not typically recommended, risk-reducing removal of the ovaries and fallopian tubes may be considered, especially after age 50.
Pancreatic cancer surveillance may be considered for PALB2 carriers who have a family history of the disease. This screening, often conducted through endoscopic ultrasound or magnetic resonance cholangiopancreatography, is ideally done in the context of a clinical trial due to the evolving nature of the protocols. The goal of personalized surveillance is to use the genetic information to intervene early and improve outcomes.