ArticleNucleic acids research2019
A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 55 citations in OpenAlex.
- The Genetic and Molecular Analyses of Rare Candidate GermlineInternational journal of molecular sciences · 2026Article
- Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.Nature communications · 2026Article
- 53BP1-RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes.Nature communications · 2025Article
- Germline Mutations in DNA Repair Genes in Patients with Pancreatic Neuroendocrine Neoplasms: Diagnostic and Therapeutic Implications.Current oncology (Toronto, Ont.) · 2025Article
- Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.American journal of human genetics · 2025Article
- Exploring the Potential of Homologous Recombination Protein PALB2 in Synthetic Lethal Combinations.ACS chemical biology · 2025Article
- Structural analysis of genetic variants of the human tumor suppressor PALB2 coiled-coil domain.Bioscience reports · 2025Article
- Hodgkin lymphoma and Ewing sarcoma in pediatric patient carrying germlineFrontiers in oncology · 2025Article
- Proline variants in the BRCA1 coiled-coil domain disrupt folding and binding to PALB2.Protein science : a publication of the Protein Society · 2025Article
- Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.Cancer research · 2023Article
- Estimating clinical risk in gene regions from population sequencing cohort data.American journal of human genetics · 2023Article
- Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank.American journal of human genetics · 2023Article
- Estimating clinical risk in gene regions from population sequencing cohort data.medRxiv : the preprint server for health sciences · 2023Article
- O-GlcNAc transferase is important for homology-directed repair.DNA repair · 2022Article
- KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity.eLife · 2022Article
- Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.Human mutation · 2022Article
- BRCA1-Dependent and Independent Recruitment of PALB2-BRCA2-RAD51 in the DNA Damage Response and Cancer.Cancer research · 2022Review
- Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.NPJ breast cancer · 2022Article
- The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened.Nature communications · 2022Article
- Breast cancer risks associated with missense variants in breast cancer susceptibility genes.Genome medicine · 2022Article
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15 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
While biallelic mutations in the PALB2 tumor suppressor cause Fanconi anemia subtype FA-N, monoallelic mutations predispose to breast and familial pancreatic cancer. Although hundreds of missense variants in PALB2 have been identified in patients to date, only a few have clear functional and clinical relevance. Herein, we investigate the effects of 44 PALB2 variants of uncertain significance found in breast cancer patients and provide detailed analysis by systematic functional assays. Our comprehensive functional analysis reveals two hotspots for potentially deleterious variations within PALB2, one at each terminus. PALB2 N-terminus variants p.P8L [c.23C>T], p.Y28C [c.83A>G], and p.R37H [c.110G>A] compromised PALB2-mediated homologous recombination. At the C-terminus, PALB2 variants p.L947F [c.2841G>T], p.L947S [c.2840T>C], and most strikingly p.T1030I [c.3089C>T] and p.W1140G [c.3418T>C], stood out with pronounced PARP inhibitor sensitivity and cytoplasmic accumulation in addition to marked defects in recruitment to DNA damage sites, interaction with BRCA2 and homologous recombination. Altogether, our findings show that a combination of functional assays is necessary to assess the impact of germline missense variants on PALB2 function, in order to guide proper classification of their deleteriousness.
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