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A 42-year-old woman is diagnosed with invasive ductal breast cancer. Her sister was diagnosed with breast cancer at 39, and her maternal aunt died of pancreatic cancer at 58. Multi-gene panel testing identifies a pathogenic variant in PALB2.
AD (cancer predisposition); AR (Fanconi anemia subtype N)
- PALB2 (16p12.2): Partner And Localizer of BRCA2
- Encodes a protein that colocalizes with BRCA2 in nuclear foci and is essential for BRCA2-mediated homologous recombination DNA repair
- Heterozygous pathogenic variants confer a moderate-to-high cancer predisposition
- Biallelic pathogenic variants cause Fanconi anemia complementation group N (FA-N), a severe childhood cancer predisposition syndrome
Cancer Risks (approximate lifetime):
| Cancer | Risk |
|---|---|
| Breast | 33-58% |
| Pancreatic | 2-3x general population |
| Ovarian | Modestly elevated |
- Moderate-to-high penetrance breast cancer gene
- Breast cancer risk is age-dependent and modified by family history
- Elevated pancreatic cancer risk (2-3x general population)
- Modestly elevated ovarian cancer risk (less well-defined than BRCA1/2)
- No clearly established association with prostate cancer
- Variable penetrance influenced by family history and other genetic modifiers
- Multi-gene panel testing (PALB2 is included on most hereditary breast cancer panels)
- Testing criteria are similar to BRCA1/2 (early-onset breast cancer, family history of breast or pancreatic cancer)
- NCCN guidelines now classify PALB2 as a high-penetrance gene warranting clinical action
- Enhanced breast surveillance: annual mammography plus breast MRI starting at age 30
- Discussion of risk-reducing mastectomy based on family history and individual risk assessment
- Pancreatic cancer screening (EUS/MRCP) if there is a family history of pancreatic cancer
- No specific ovarian cancer screening guidelines for PALB2 carriers at this time
- PARP inhibitors may be effective for PALB2-associated cancers (given role in homologous recombination)
- Cascade testing recommended for at-risk relatives
"PALB2 = PAncreatic & Breast": PALB2 increases risk for Pancreatic and Breast cancer. When you have your "PAL", the 2 ovaries are activated (modestly elevated ovarian cancer risk).
PALB2 is the Partner And Localizer of BRCA2: PALB2 colocalizes with BRCA2 for homologous recombination. Heterozygous (AD) = cancer predisposition; biallelic (AR) = Fanconi anemia subtype N.