PALB2

PALB2 (partner and localizer of BRCA2) is a human gene that encodes the PALB2 protein, a key coordinator of the BRCA1–BRCA2-mediated pathway for repairing DNA double-strand breaks by homologous recombination. The PALB2 protein interacts with BRCA1 and BRCA2 and helps localize BRCA2 to sites of DNA damage, facilitating recruitment of RAD51 and efficient repair. Loss of PALB2 function leads to genomic instability and increased cancer susceptibility.

The PALB2 gene is located on chromosome 16q24.1 and encodes a protein with domains that mediate protein–protein interactions. Pathogenic variants in PALB2 can be truncating or missense and are inherited in an autosomal dominant manner with incomplete penetrance.

Heterozygous PALB2 pathogenic variants are associated with an increased risk of breast cancer, and there is evidence for elevated risks of pancreatic cancer and possibly ovarian cancer. Biallelic PALB2 mutations (two mutated copies) cause Fanconi anemia, complementation group FA-N, a constitutional disorder characterized by bone marrow failure and developmental abnormalities; these individuals also have a predisposition to malignancies.

In clinical practice, PALB2 is considered a moderate-penetrance breast cancer susceptibility gene. Genetic testing is offered in families with a history of breast, pancreatic, or ovarian cancer, particularly when BRCA1/2 testing is negative or inconclusive. Management may include enhanced breast cancer surveillance (annual MRI and mammography starting at an early age) and discussion of risk-reducing options depending on overall risk assessment.