ArticleHuman molecular genetics2012
Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 66 citations in OpenAlex.
- Article
- Functional assays for BRCA1 and BRCA2 variant analysis: new tools and their applications.NPJ breast cancer · 2026Review
- Modelling DMC1 mediated homologous recombination repair in mouse embryonic stem cells.Frontiers in cell and developmental biology · 2026Article
- Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination.Communications biology · 2025Article
- BRCA2 stabilises RAD51 and DMC1 nucleoprotein filaments through a conserved interaction mode.Nature communications · 2024Article
- The BRCA2 R2645G variant increases DNA binding and induces hyper-recombination.Nucleic acids research · 2024Article
- DMC1 and RAD51 bind FxxA and FxPP motifs of BRCA2 via two separate interfaces.Nucleic acids research · 2024Article
- The Molecular Detection of Germline Mutations in theCurrent issues in molecular biology · 2024Article
- Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.American journal of human genetics · 2024Article
- Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.Cell reports methods · 2023Article
- Saturation genome editing of 11 codons and exon 13 of BRCA2 coupled with chemotherapeutic drug response accurately determines pathogenicity of variants.PLoS genetics · 2023Article
- Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.Human mutation · 2022Article
- Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.Human mutation · 2022Article
- Article
- Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.Scientific reports · 2022Article
- Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2).Cancer genetics · 2021Article
- Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.American journal of human genetics · 2021Article
- Guardians of the Genome: BRCA2 and Its Partners.Genes · 2021Review
- Review
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 1 country.
Funding
Abstract
Single-nucleotide substitutions and small in-frame insertions or deletions identified in human breast cancer susceptibility genes BRCA1 and BRCA2 are frequently classified as variants of unknown clinical significance (VUS) due to the availability of very limited information about their functional consequences. Such variants can most reliably be classified as pathogenic or non-pathogenic based on the data of their co-segregation with breast cancer in affected families and/or their co-occurrence with a pathogenic mutation. Biological assays that examine the effect of variants on protein function can provide important information that can be used in conjunction with available familial data to determine the pathogenicity of VUS. In this report, we have used a previously described mouse embryonic stem (mES) cell-based functional assay to characterize eight BRCA2 VUS that affect highly conserved amino acid residues and map to the N-terminal PALB2-binding or the C-terminal DNA-binding domains. For several of these variants, very limited co-segregation information is available, making it difficult to determine their pathogenicity. Based on their ability to rescue the lethality of Brca2-deficient mES cells and their effect on sensitivity to DNA-damaging agents, homologous recombination and genomic integrity, we have classified these variants as pathogenic or non-pathogenic. In addition, we have used homology-based modeling as a predictive tool to assess the effect of some of these variants on the structural integrity of the C-terminal DNA-binding domain and also generated a knock-in mouse model to analyze the physiological significance of a residue reported to be essential for the interaction of BRCA2 with meiosis-specific recombinase, DMC1.
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