PALB2 – Hereditary Breast Carcinoma

PALB2 (Partner and Localizer of BRCA2) is a tumor suppressor that bridges BRCA1 and BRCA2 in homologous recombination (HR)–mediated repair of DNA double-strand breaks. Loss-of-function (LoF) variants in PALB2 compromise RAD51 filament formation and HR efficiency, predisposing carriers to hereditary breast carcinoma. PALB2 is inherited in an autosomal dominant pattern with incomplete penetrance linked to haploinsufficiency of HR repair.

Multiple case–control and panel-based studies demonstrate an excess of LoF PALB2 variants in familial breast cancer. In a series of 2,000 BRCA1/2-negative index cases versus 1,997 controls, PALB2 pathogenic alleles were found in 26 cases and 4 controls (OR≈2.5) ([PMID:26786923]). Sanger sequencing of 1,479 high-risk, BRCA1/2-negative patients identified 12 truncating PALB2 mutations (0.8% prevalence; 1.05% in “high-risk” subgroup) ([PMID:24415441]). Extended screening in Japanese and Russian cohorts detected recurrent LoF PALB2 alleles in 0.7–1.6% of breast cancer cases ([PMID:30287823]; [PMID:32997802]).

Segregation analysis further supports pathogenicity: in one series of 68 BRCA1/2-negative families of diverse descent, a PALB2 229delT truncation co-segregated with seven breast cancers in three female carriers (no loss of heterozygosity in tumors) ([PMID:17420451]). This multi-family evidence underscores the penetrance of PALB2 LoF variants.

The PALB2 variant spectrum is dominated by nonsense and frameshift mutations, with key pathogenic alleles including c.104T>C (p.Leu35Pro) ([PMID:28319063]), c.1592del (p.Leu531CysfsTer30) ([PMID:20003494]), and c.229del (p.Cys77ValfsTer?) ([PMID:17420451]). These variants disrupt PALB2’s coiled-coil or WD40 domains, abrogating interactions with BRCA1/2 and RAD51.

Functional studies reveal that PALB2 is essential for loading BRCA2 and RAD51 onto chromatin at damage sites. PALB2 binds directly to BRCA1 via coiled-coil domains and to BRCA2 through its WD40 repeats; cancer-associated mutations in these interfaces impair HR and sensitize cells to DNA crosslinkers ([PMID:19369211]; [PMID:28319063]). A phospho-deficient PALB2 mutant exhibits defective RAD51 focus formation, highlighting regulation by ATM/ATR phosphorylation ([PMID:27113759]).

Mechanistically, heterozygous PALB2 LoF shifts repair toward error-prone pathways: carriers of c.1592del show increased single-strand annealing and microhomology-mediated end-joining without consistent reduction in HR, evidencing haploinsufficiency in DSB repair fidelity ([PMID:26640152]).

Together, genetic and experimental data establish a strong gene-disease validity for PALB2 in hereditary breast carcinoma. PALB2 testing refines risk stratification and guides clinical management, including MRI surveillance and consideration of platinum or PARP inhibitor therapy for mutation carriers.

References

• Journal of clinical oncology • 2016 • Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care. PMID:26786923
• Cancer • 2014 • Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer. PMID:24415441
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • Analysis of PALB2/FANCN-associated breast cancer families. PMID:17420451
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • PALB2 is an integral component of the BRCA complex required for homologous recombination repair. PMID:19369211
• Oncogene • 2017 • Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. PMID:28319063
• Oncogene • 2016 • Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients. PMID:26640152

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