ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Functional characterization of 84 PALB2 variants of uncertain significance.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- From mutation to treatment: The dual role of BRCA1 and BRCA2 in gynecological malignancy development and management a systematic review.Biochemistry and biophysics reports · 2026Review
- Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.Nature communications · 2026Article
- 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
- Proline variants in the BRCA1 coiled-coil domain disrupt folding and binding to PALB2.Protein science : a publication of the Protein Society · 2025Article
- Hodgkin lymphoma and Ewing sarcoma in pediatric patient carrying germlineFrontiers in oncology · 2025Article
- Using AI-predicted protein structures as a reference to predict loss-of-function activity in tumor suppressor breast cancer genes.Computational and structural biotechnology journal · 2024Article
- Germline Variant Spectrum in Southern Italian High-Risk Hereditary Breast Cancer Patients: Insights from Multi-Gene Panel Testing.Current issues in molecular biology · 2024Article
- Whole exome sequencing of a novel homozygous missense variant inBiomedical reports · 2024Article
- Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.DNA repair · 2023Review
- Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.Cancer research · 2023Article
- KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity.eLife · 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
- Breast cancer risks associated with missense variants in breast cancer susceptibility genes.Genome medicine · 2022Article
- Characterisation of protein-truncating and missense variants inJournal of medical genetics · 2022Article
- Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants.The Journal of pathology · 2022Article
- Hereditary variants of unknown significance in African American women with breast cancer.PloS one · 2022Article
- A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene.Genome medicine · 2021Article
- Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance.NPJ genomic medicine · 2021Article
Corrections and comments
- Commented on by
Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
purposeInherited pathogenic variants in PALB2 are associated with increased risk of breast and pancreatic cancer. However, the functional and clinical relevance of many missense variants of uncertain significance (VUS) identified through clinical genetic testing is unclear. The ability of patient-derived germline missense VUS to disrupt PALB2 function was assessed to identify variants with potential clinical relevance.
methodsThe influence of 84 VUS on PALB2 function was evaluated using a cellular homology directed DNA repair (HDR) assay and VUS impacting activity were further characterized using secondary functional assays.
resultsFour (~5%) variants (p.L24S,c.71T>C; p.L35P,c.104T>C; pI944N,c.2831T>A; and p.L1070P,c.3209T>C) disrupted PALB2-mediated HDR activity. These variants conferred sensitivity to cisplatin and a poly(ADP-ribose) polymerase (PARP) inhibitor and reduced RAD51 foci formation in response to DNA damage. The p.L24S and p.L35P variants disrupted BRCA1-PALB2 protein complexes, p.I944N was associated with protein instability, and both p.I944N and p.L1070P mislocalized PALB2 to the cytoplasm.
conclusionThese findings show that the HDR assay is an effective method for screening the influence of inherited variants on PALB2 function, that four missense variants impact PALB2 function and may influence cancer risk and response to therapy, and suggest that few inherited PALB2 missense variants disrupt PALB2 function in DNA repair.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.