GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions

|ailure of FA pathway coordination causes Fanconi anemia complementation group N, characterized by bone marrow failure, developmental abnormalities, and early-onset malignancies<ref name=":2" /><ref name=":13">Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref>

Recommended testing approaches for ''PALB2'' include comprehensive germline sequencing with concurrent copy number analysis. Next generation sequencing (NGS) based multigene hereditary cancer panels or targeted PALB2 sequencing are the primary diagnostic methods to identify clinically significant variants, including pathogenic single-nucleotide variants (SNVs), small insertions/deletions (indels), and canonical splice-site alterations<ref name=":14">Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506.</ref><ref name=":15">Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86</ref>. Because exonic and whole gene deletions or duplications represent a clinically relevant subset of pathogenic ''PALB2'' variants, copy number variant (CNV) analysis should be performed as part of routine testing. CNV detection may be achieved using NGS read-depth algorithms, multiplex ligation dependent probe amplification (MLPA), or chromosomal microarray (CMA) when appropriate<ref name=":16">lavin TP, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017;3:22.</ref><ref name=":17">National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024</ref>. For individuals with a strong personal or family history suggestive of hereditary breast, ovarian, or pancreatic cancer and negative standard testing, RNA analysis may be considered to clarify the functional impact of suspected splice-altering variants or deep intronic changes <ref name=":18">Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.</ref>. When ''PALB2'' variants are identified through tumor only genomic testing, paired germline testing is recommended to distinguish germline pathogenic variants from somatic alterations and to inform clinical management, cascade testing, and cancer risk assessment for at-risk relatives<ref name=":19">Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424</ref><ref name=":17" />.

Pathogenic variants in ''PALB2'' are associated with hereditary breast cancer susceptibility and confer a moderate to high lifetime risk of breast cancer, with risk estimates approaching those observed for ''BRCA2'' in some families<ref name=":14" /><ref name=":15" />. Female carriers have an estimated 35–58% lifetime risk of breast cancer by age 70, with risk modified by family history and other genetic or environmental factors. ''PALB2'' pathogenic variants are also associated with an increased risk of pancreatic cancer, and emerging evidence suggests a possible association with ovarian cancer, although penetrance for non-breast cancers remains lower and less well defined compared with BRCA1/2<ref name=":5" /><ref name=":17" />. Biallelic pathogenic variants in ''PALB2'' cause Fanconi anemia subtype N, characterized by congenital anomalies, bone marrow failure, and childhood cancer predisposition, highlighting the gene’s essential role in DNA repair<ref name=":13" />. From a molecular standpoint, PALB2 encodes a critical partner of BRCA1 and BRCA2 within the homologous recombination (HR) DNA repair pathway. Loss of function variants result in homologous recombination deficiency (HRD), which has therapeutic relevance, as tumors harboring germline or somatic ''PALB2'' pathogenic variants may demonstrate sensitivity to PARP inhibitors and platinum based chemotherapy<ref name=":20">Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.</ref><ref name=":21">Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.</ref>. Identification of a pathogenic ''PALB2'' variant has important clinical management implications, including enhanced breast cancer surveillance (e.g., annual breast MRI), consideration of risk reducing strategies, and cascade testing for at risk relatives, in accordance with established professional guidelines<ref name=":17" />.