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PALB2

PALB2, or Partner and Localizer of BRCA2, is a human gene located on chromosome 16p12.2 that encodes a nuclear protein critical for maintaining genomic stability through its role in DNA damage repair, particularly homologous recombination (HR) of double-strand breaks.^[1] The PALB2 protein acts as a bridging factor, binding to BRCA1 via its N-terminal coiled-coil domain and to BRCA2 via a C-terminal binding site, thereby facilitating the recruitment of RAD51 recombinase to sites of DNA damage and promoting error-free repair.^[2] As a key component of the Fanconi anemia (FA) pathway, specifically the FA-N complementation group, PALB2 also interacts with proteins like RAD51, MRG15, and polymerases to coordinate repair processes during replication stress and interstrand crosslinks.^[2] Germline mutations in PALB2 predispose individuals to hereditary cancers, functioning as a tumor suppressor gene with autosomal dominant inheritance for cancer risk.^[1] Heterozygous truncating mutations confer a substantially elevated lifetime risk of breast cancer in women, estimated at 35–58% (compared to 12% in the general population), with risks approaching those associated with BRCA2 mutations (45–69%), and often presenting as estrogen receptor-positive tumors or triple-negative subtypes.^[3] These mutations also increase risks for pancreatic cancer (1–5% lifetime), ovarian cancer (2–10%), prostate cancer, male breast cancer, and melanoma, while biallelic mutations cause the rare FA-N subtype of Fanconi anemia, characterized by congenital abnormalities and heightened leukemia risk.^[1]^[2] Clinically, PALB2 mutations are rare (prevalence 0.1–2.7% in breast cancer patients) but actionable, as HR-deficient tumors arising from these defects show sensitivity to platinum-based chemotherapy and PARP inhibitors, similar to BRCA-mutated cancers.^[3] Genetic testing for PALB2 is recommended for individuals with family histories of related cancers, enabling risk assessment and preventive strategies like enhanced screening or prophylactic measures.^[3] Ongoing research highlights specific missense variants, such as L35P (disrupting BRCA1 binding) and A1025R (impairing BRCA2 interaction), which compromise repair efficiency and contribute to oncogenesis.^[2]

Genetics

Gene Structure

The PALB2 gene is located on the short arm of chromosome 16 at position 16p12.2, spanning approximately 38 kb from base pair 23,603,160 to 23,641,321 (GRCh38/hg38 assembly).^[4]^[5] It consists of 13 exons, which encode the primary coding sequence for the gene product.^[6]^[7] The primary transcript of PALB2 is a full-length mRNA of 4,008 bp, which undergoes processing to produce the canonical isoform ENST00000261584.9 (also known as NM_024675.4).^[8] This isoform translates into a protein of 1,186 amino acids. The gene exhibits alternative splicing, generating multiple transcript variants; Ensembl annotations identify 23 distinct transcripts, while broader databases report up to 39, though many are predicted and lack full functional validation.^[7]^[4]^[5] PALB2 demonstrates strong evolutionary conservation across mammalian species, with 172 orthologues identified, reflecting its essential role in genomic stability. Key motifs, such as the chromatin-association motif (ChAM), are preserved from humans to rodents and beyond, underscoring functional invariance. Regulatory elements include a core promoter region susceptible to hypermethylation and multiple enhancers mapped by GeneHancer, which influence tissue-specific transcription.^[4]^[9]^[5]^[10] Expression of PALB2 is widespread but elevated in specific tissues, with the highest levels observed in the pancreas, breast glandular cells, and gonadal germ cells such as primordial germ cells and secondary oocytes. This pattern aligns with its roles in high-proliferation contexts, as detected in RNA sequencing datasets like GTEx and Bgee.^[11]^[5]

Mutations and Variants

Mutations in the PALB2 gene are classified into several categories based on their molecular impact, including truncating mutations such as nonsense and frameshift variants that introduce premature stop codons or alter the reading frame, leading to loss-of-function proteins.^[12] Missense mutations, which substitute a single amino acid, can also be pathogenic if they disrupt critical protein domains, though many are benign or of uncertain significance.^[13] Large deletions and insertions, encompassing genomic rearrangements that remove or add substantial portions of the gene, are rarer but have been identified in screening studies of high-risk families.^[14] A notable example of a truncating frameshift mutation is c.1592delT (p.Leu534fs), a founder variant prevalent in Finnish populations.^[15] Germline PALB2 mutations occur at a low frequency in the general population, with pathogenic variants estimated at approximately 0.18% globally, equating to about 1 in 550 carriers, based on large-scale genomic databases like gnomAD.^[16] Prevalence is higher in specific ethnic groups due to founder effects; for instance, the c.1592delT variant reaches 0.41% in Finnish individuals, while rates are notably lower in Ashkenazi Jewish populations, where no major founder mutations have been established.^[17] In unselected breast cancer cohorts, germline pathogenic variants are detected in roughly 0.6-1% of cases, underscoring their role in hereditary susceptibility.^[18] Many identified PALB2 variants fall into the category of variants of uncertain significance (VUS), which cannot be definitively classified as benign or pathogenic without additional evidence. Classification follows the American College of Medical Genetics and Genomics (ACMG) guidelines, incorporating criteria such as population frequency, computational predictions, and segregation data.^[19] Recent 2025 updates to PALB2-specific ACMG/AMP guidelines emphasize the use of functional assays, including those assessing protein stability, homology-directed repair efficiency, and interactions with partner proteins, to reclassify VUS more accurately and conservatively.^[20] For example, assays like CRISPR-based editing and homology-directed repair reporter systems have helped resolve over 80 PALB2 VUS by demonstrating impaired DNA repair capacity in a subset.^[21] Somatic PALB2 mutations, acquired in tumor cells rather than inherited, differ from germline variants in both type and frequency; they often include missense changes or small indels and occur in approximately 1-2% of breast tumors, compared to 1% for germline in patient populations.^[22] Biallelic germline mutations in PALB2 cause Fanconi anemia subtype N, a rare disorder characterized by congenital anomalies and cancer predisposition.^[23]

Protein and Function

Protein Structure

The PALB2 protein, encoded by the PALB2 gene on chromosome 16p12.2, consists of 1186 amino acids and adopts a modular domain architecture critical for its structural integrity.^[24] The N-terminal region features a coiled-coil domain spanning residues 9–42, which forms an antiparallel α-helical homodimer and also enables heterodimerization with BRCA1 through a shared interface.^[25] In the central portion, residues 395–446 comprise the chromatin-association motif (ChAM), a positively charged segment that facilitates nucleosome binding via electrostatic interactions.^[26] The C-terminus harbors seven WD40 repeats (residues 853–1186), assembling into a compact β-propeller fold with seven blades, each formed by four antiparallel β-strands.^[27] Key structural motifs include the RAD51-binding domain within the C-terminal region (residues 858–1094), characterized by a helical extension adjacent to the WD40 propeller that accommodates RAD51 monomers via hydrophobic contacts.^[28] PALB2 also contains nuclear localization signals, including a bipartite NLS at residues 21–38 in the N-terminus and a monopartite NLS at residues 1104–1110 near the C-terminus, which direct its nuclear import through interactions with importin-α/β.^[24] Additionally, a nuclear export sequence (NES) at residues 928–945 within the WD40 domain allows CRM1-mediated export, contributing to spatiotemporal regulation.^[26] Post-translational modifications influence PALB2's conformational dynamics, with phosphorylation sites targeted by ATM and ATR kinases in response to DNA damage. Notable sites include Ser59, Ser157, and Ser376 in the N- and central regions, where phosphorylation introduces negative charges that may alter domain accessibility and protein interactions.^[29] These modifications are conserved across species and cluster in intrinsically disordered regions flanking the structured domains.^[26] High-resolution crystal structures illuminate PALB2's interaction interfaces, particularly the C-terminal WD40 domain in complex with a BRCA2 peptide (PDB ID: 3EU7, resolved at 2.5 Å). This structure reveals a central tunnel in the β-propeller where the BRCA2 peptide binds via Phe-Pro hydrophobic motifs on blade 6, stabilizing a 1:1 heterodimer; mutations at this interface disrupt association.^[30] The N-terminal coiled-coil domain's solution structure (NMR, PDB ID: 7T0Z) confirms its dimeric α-helical bundle, with leucine residues at the interface driving hydrophobic packing.^[25] These atomic models highlight PALB2's scaffold-like architecture, integrating binding surfaces across its length.^[27]

Role in DNA Repair

PALB2 functions as a scaffold protein in homologous recombination (HR), a key pathway for repairing DNA double-strand breaks (DSBs) in an error-free manner. It stabilizes BRCA2-RAD51 nucleoprotein filaments at DSB sites by bridging BRCA1 and BRCA2, thereby facilitating the loading of RAD51 recombinase onto single-stranded DNA (ssDNA) after end resection. This stabilization is essential for RAD51-mediated strand invasion and homology-directed repair, preventing genomic instability.^[31]^[32] In the HR pathway, PALB2 is recruited to DSBs primarily through its interaction with BRCA1, which is phosphorylated during the S/G2 phases of the cell cycle to enhance this association. Once at the damage site, PALB2 promotes the displacement of replication protein A (RPA) from ssDNA and aids BRCA2 in nucleating RAD51 filaments, enabling accurate repair via mechanisms such as double Holliday junction dissolution or synthesis-dependent strand annealing. This coordinated action ensures precise restoration of the DNA sequence, contrasting with error-prone alternatives like non-homologous end joining.^[33]^[32] PALB2, designated as FANCN in the Fanconi anemia (FA) pathway, also contributes to the repair of interstrand crosslinks (ICLs) by integrating HR with FA mechanisms. It coordinates with the monoubiquitinated FANCD2-FANCI complex to direct HR at stalled replication forks, where ICL unhooking generates one-ended DSBs that PALB2-BRCA2 help resolve through RAD51 filament formation. This role links the FA and HR pathways, maintaining replication fidelity during genotoxic stress.^[34] Experimental evidence from PALB2 knockout models, such as mutant mouse embryonic fibroblasts, demonstrates hypersensitivity to DNA-damaging agents like mitomycin C, which induces ICLs and reveals defects in HR and FA-mediated repair through increased chromosomal aberrations and cell death.^[35] Recent studies from 2024-2025 have further elucidated synthetic lethality in PALB2-deficient cells with PARP inhibitors, which trap PARP on DNA and overwhelm residual repair capacity, leading to DSB accumulation and cell lethality in HR-compromised backgrounds. These findings underscore PALB2's central role in DSB repair fidelity.^[36]

Role in Meiosis

Meiotic Recombination

PALB2 plays a critical role in homologous recombination (HR) during meiosis, particularly in germ cells where it facilitates the repair of programmed double-strand breaks (DSBs) to ensure proper chromosome segregation. In meiotic prophase I, PALB2 coordinates with BRCA1 to recruit BRCA2, which in turn loads the recombinases RAD51 and the meiosis-specific DMC1 onto resected DSB ends, enabling strand invasion and repair using the homologous chromosome as a template. This process is essential for synaptonemal complex (SC) formation, as evidenced by reduced DMC1 and RAD51 foci in germ cells with disrupted PALB2-BRCA1 interactions, leading to defective SC assembly and chromosome synapsis.^[37]^[38]^[39] The meiotic DSBs repaired by this PALB2-BRCA2-RAD51 axis are deliberately induced by the SPO11 protein at numerous hotspots across the genome, contrasting with sporadic mitotic DSBs. PALB2's involvement ensures efficient crossover resolution, marked by MLH1 foci, which are significantly diminished in PALB2-deficient meiocytes, resulting in fewer reciprocal exchanges between homologs. Studies in mice with mutations disrupting the PALB2 coiled-coil domain, which impairs its interaction with BRCA1, demonstrate this coordination: mutant spermatocytes exhibit fewer RAD51/DMC1 foci and reduced MLH1 signals, alongside asynapsed chromosomes and elevated germ cell apoptosis, culminating in subfertile males with smaller testes and impaired sperm production. These findings highlight PALB2's necessity for resolving the high frequency of SPO11-induced DSBs into viable crossovers.^[38]^[37] This meiotic function of PALB2 is conserved in humans, where variants in PALB2 have been implicated in reproductive disorders through genome-wide association studies and sequencing of infertility cohorts. A 2025 analysis of men with severe oligozoospermia revealed a significantly enriched burden of germline variants in hereditary cancer genes, including PALB2, compared to fertile controls, suggesting a role in meiotic defects leading to spermatogenic failure. Similarly, biallelic loss-of-function variants in related HR genes like BRCA2, which interact with PALB2, have been linked to premature ovarian insufficiency via impaired meiotic HR in a 2025 study using mouse models informed by patient variants, underscoring the pathway's relevance to human germ cell integrity.^[40]^[41] Unlike mitotic HR, where PALB2 primarily repairs accidental DSBs using sister chromatids with low frequency and minimal crossover outcomes, meiotic HR mediated by PALB2 emphasizes inter-homolog bias to generate obligatory crossovers for chiasma formation, handling hundreds of SPO11-induced DSBs per meiosis to promote genetic diversity and accurate segregation. This adaptation involves meiosis-specific regulators like DMC1, which PALB2 indirectly supports via BRCA2, ensuring crossover designation and resolution while suppressing non-allelic exchanges that could lead to aneuploidy. Mouse models with PALB2 pathway disruptions exhibit increased unpaired chromosomes and potential aneuploid gametes, mirroring human infertility risks associated with these variants.^[42]^[37]^[40]

Fertility Implications

Biallelic pathogenic mutations in the PALB2 gene cause Fanconi anemia complementation group N (FA-N), a subtype of Fanconi anemia characterized by bone marrow failure, congenital anomalies, and heightened cancer predisposition.^[43] Individuals with FA-N often develop gonadal atrophy due to the underlying DNA repair deficiency, resulting in infertility across both sexes.^[44] In females, this manifests as premature ovarian insufficiency, delayed puberty, irregular menses, and reduced fertility, while males typically exhibit hypogonadism and azoospermia, leading to sterility.^[45] These reproductive complications arise from disrupted primordial germ cell development and increased apoptosis during gametogenesis, contributing to a shortened reproductive lifespan in affected patients.^[46] Heterozygous (monallelic) PALB2 mutations, while primarily linked to cancer risk, are also associated with subfertility phenotypes, including diminished ovarian reserve in female carriers.^[47] A 2025 clinical study evaluating ovarian reserve markers in young women carrying pathogenic variants in hereditary breast and ovarian cancer syndrome genes, including PALB2, reported trends of lower anti-Müllerian hormone levels and reduced antral follicle counts, indicating potential early depletion of ovarian follicles and impaired fertility.^[47] Although sample sizes for PALB2 specifically were limited (n=2), these findings align with broader observations in DNA repair gene carriers. Increased miscarriage risk has been noted anecdotally in such carriers, potentially due to embryonic DNA repair vulnerabilities, though direct PALB2-specific data remain sparse.^[48] For PALB2 mutation carriers planning families, preimplantation genetic diagnosis (PGD) offers a reproductive option through in vitro fertilization, enabling selection of embryos without the pathogenic variant to mitigate transmission risks.^[49] This approach is particularly relevant for heterozygous carriers concerned about biallelic inheritance in offspring, which could lead to FA-N.^[50] Clinical guidelines recommend genetic counseling to discuss PGD feasibility, success rates (typically 20-40% per cycle depending on maternal age), and ethical considerations.^[49] Insights from animal models underscore these human observations, with Palb2-deficient mice exhibiting oogenesis defects linked to meiotic recombination failures.^[51] Although complete Palb2 knockout is embryonically lethal, hypomorphic alleles and conditional models reveal increased germ cell loss and impaired oocyte maturation due to unresolved DNA double-strand breaks during meiosis, mirroring subfertility patterns in carriers.^[51] These findings highlight PALB2's critical role in maintaining genomic integrity for successful gametogenesis.^[51]

Clinical Significance

Associated Cancers

Germline pathogenic variants in the PALB2 gene confer a significantly elevated risk of breast cancer, with lifetime risks estimated at 40% to 60% for female carriers, depending on family history and other factors.^[52] In males, the lifetime risk of breast cancer is approximately 1%, representing an emerging association second only to BRCA2 mutations among hereditary breast cancer genes.^[53] These risks are supported by large cohort studies, including the PALB2 International Collaborative Group analysis of 524 families, which reported a cumulative incidence of 52.8% by age 80 for female breast cancer.^[52] PALB2 variants are also linked to increased risks of ovarian and pancreatic cancers. For ovarian cancer, the lifetime risk is approximately 5%, with odds ratios ranging from 2.13 to 10.2 across studies.^[52] Pancreatic cancer risk shows a 5- to 10-fold increase, translating to a 5% to 10% lifetime risk, as evidenced by relative risks of 2.4 in prospective cohorts.^[52] Emerging evidence suggests an association with prostate cancer, with odds ratios around 3 in some studies.^[54] Penetrance of PALB2-related cancer risks is modified by factors such as family history, which can elevate breast cancer risk to 58% in carriers with two or more first-degree relatives with early-onset breast cancer.^[52] Epidemiological data indicate that PALB2 pathogenic variants account for 3% to 5% of cases in hereditary breast cancer panels among high-risk families, highlighting their role in non-BRCA hereditary syndromes.^[55]

Genetic Testing and Management

Genetic testing for PALB2 pathogenic variants is recommended as part of multigene panel testing for individuals with a personal or family history of breast, ovarian, or pancreatic cancer that meets hereditary cancer criteria, according to the National Comprehensive Cancer Network (NCCN) guidelines.^[56] Cascade testing is advised for at-risk relatives of identified carriers to facilitate early risk assessment and management.^[56] The National Cancer Institute's Physician Data Query (PDQ) summary emphasizes that PALB2 is included in all standard multigene panels for breast cancer susceptibility.^[52] For risk management, carriers of PALB2 pathogenic variants face elevated lifetime risks of breast cancer (approximately 53% by age 80), pancreatic cancer (5-10%), and ovarian cancer (around 5%), warranting enhanced surveillance and preventive options.^[52] Breast cancer screening typically involves annual mammography combined with breast MRI starting at age 30, as per NCCN and PDQ recommendations.^[56]^[52] Risk-reducing bilateral mastectomy is an option to substantially lower breast cancer incidence, achieving approximately 90% risk reduction in high-risk individuals similar to those with BRCA1/2 variants.^[57] For ovarian cancer prevention, risk-reducing salpingo-oophorectomy is considered around ages 45-50, though evidence is less robust than for BRCA mutations.^[52] Pancreatic cancer surveillance includes MRI with magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound beginning at age 50, or 10 years prior to the earliest family diagnosis, ideally in high-volume centers.^[56]^[52] Therapeutically, tumors with PALB2 mutations exhibit sensitivity to PARP inhibitors, such as olaparib, which has demonstrated clinical activity in phase II trials for metastatic breast and pancreatic cancers harboring these variants.^[52]^[58] Additionally, PALB2-mutated cancers show increased responsiveness to platinum-based chemotherapy due to impaired homologous recombination repair.^[52]^[59] Ethical considerations in PALB2 testing include comprehensive counseling for variants of uncertain significance (VUS), where clinicians must explain that such findings do not alter management but may evolve with reclassification, emphasizing shared decision-making to mitigate psychological distress.^[60] Reproductive options, such as preimplantation genetic diagnosis (PGD) during in vitro fertilization, allow carriers to select embryos without the PALB2 variant, reducing transmission risk while addressing family planning concerns.^[61]^[62]

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Dec 2, 2019 · Clinically, breast and ovarian cancers associated with BRCA1 and BRCA2 mutations show heightened sensitivity to platinum-based chemotherapy.
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Cancer Genetics Risk Assessment and Counseling (PDQ®) - NCBI
Jan 3, 2025 · Having an understanding of the ethical, legal, and social implications regarding cancer genetic testing may influence the clinician's response ...
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Preimplantation Genetic Testing - Breast Cancer.org
Nov 2, 2023 · Preimplantation genetic testing (PGT) refers to all types of genetic testing on embryos, including PGD. Find out if it's right for you.Missing: PALB2 | Show results with:PALB2
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ICARE Social Media Post April 2020: PALB2 Cancer Risks
PGD is a procedure available for certain gene mutations to screen the embryo prior to achievement of pregnancy.