The PALB2 gene (Partner and Localizer of BRCA2) is a significant factor in hereditary cancer risk. When this gene contains a pathogenic variant, the body’s ability to repair damaged DNA is compromised. This failure leads to genomic instability, which substantially increases an individual’s susceptibility to developing certain types of cancer over their lifetime.
The Role of the PALB2 Gene
The PALB2 gene product acts as a helper protein in DNA damage repair. Its primary function is to work directly with the BRCA2 protein, forming a bridge that connects to the BRCA1 protein. This collaborative effort is responsible for homologous recombination, a highly accurate pathway that fixes double-stranded breaks in the DNA helix.
When a pathogenic variant occurs in the PALB2 gene, the resulting protein is either non-functional or entirely absent. Consequently, the DNA repair machinery cannot operate correctly, allowing errors to accumulate in the genome. These unrepaired errors ultimately drive the formation of cancerous tumors.
Prevalence of PALB2 Pathogenic Variants
Determining the exact frequency of a pathogenic PALB2 variant in the general population is challenging, but current estimates suggest it is quite rare. Population studies indicate the variant is present in likely less than one in 1,000 individuals. This frequency can vary based on ancestry or geographic region, as certain populations may have specific founder mutations.
The prevalence rises significantly when looking at specific groups, particularly those with a personal or family history of cancer. Among women newly diagnosed with breast cancer and referred for genetic testing, the prevalence of a pathogenic PALB2 variant is consistently reported to be around 0.9% to 1.2%. This means the variant is roughly 10 times more common in this cohort than in the general population.
The variant is even more frequently detected in individuals with a strong family history of breast, ovarian, or pancreatic cancer. This concentration illustrates why genetic testing is targeted toward individuals with specific clinical criteria rather than widespread population screening. The PALB2 variant is recognized as one of the most common causes of inherited breast cancer risk after the BRCA1 and BRCA2 genes. In some hereditary cancer cohorts, its contribution can be comparable to that of BRCA1 or BRCA2.
Lifetime Cancer Risks Associated with PALB2
A pathogenic PALB2 variant carries a substantially elevated lifetime risk for developing certain cancers, with the risk for breast cancer being the most pronounced. Women who inherit this variant face an estimated lifetime risk of breast cancer ranging from 32% to 63% by age 80. This is a marked increase compared to the general female population’s lifetime risk of approximately 12%.
The level of risk can be influenced by the carrier’s family history of breast cancer; a strong family history may push the risk toward the higher end of the estimated range. Men who carry the PALB2 variant also have an elevated risk for male breast cancer, with lifetime estimates typically falling between 0.9% and 5%. While this risk is low in absolute terms, it represents a significant increase compared to the general male population risk of less than 0.1%.
Beyond breast cancer, the variant is associated with an increased risk for pancreatic cancer, with a lifetime risk estimated between 2% and 5%. This is a notable elevation compared to the general population risk, which is typically less than 1.7%. The risk for ovarian cancer is also moderately increased, with estimates suggesting a lifetime risk of approximately 3% to 5%. This risk is lower than the risk associated with BRCA1 or BRCA2 variants.
Screening and Management Recommendations
Carriers of a pathogenic PALB2 variant are advised to follow enhanced cancer surveillance protocols designed to detect cancer at its earliest stage. For women, this typically involves starting breast screening at an earlier age, usually around 30. Screening uses a combination of annual mammography and annual breast magnetic resonance imaging (MRI) with contrast. This dual approach provides the highest sensitivity for detecting tumors in high-risk individuals.
Risk-reducing surgical options are also available to carriers as a means of proactively lowering their cancer incidence. A prophylactic bilateral mastectomy, which removes both breasts, can reduce the breast cancer risk by over 90%. Removal of the ovaries and fallopian tubes, known as a risk-reducing salpingo-oophorectomy, is often considered for women between the ages of 45 and 50 to manage the elevated ovarian cancer risk.
In addition to intensive surveillance, chemoprevention drugs may be discussed with a specialist to further reduce breast cancer risk for some carriers. Comprehensive genetic counseling is an important step following a positive test result. A genetic counselor helps carriers understand their personal risk profile, discusses the implications for family members, and facilitates cascade testing to identify other relatives who may also carry the variant.