ArticleThe Journal of biological chemistry2010
Toward classification of BRCA1 missense variants using a biophysical approach.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- HSP90 buffers deleterious genetic variations in BRCA1.Molecular cell · 2025Article
- Profiling BRCA1-BRCT interactions and their functional relevance at amino acid resolution.Nucleic acids research · 2025Article
- Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers.Cell reports · 2024Article
- The complex impact of cancer-related missense mutations on the stability and on the biophysical and biochemical properties of MAPK1 and MAPK3 somatic variants.Human genomics · 2023Article
- Mutation in the Common Docking Domain Affects MAP Kinase ERK2 Catalysis and Stability.Cancers · 2023Article
- Functional analyses of rare germline BRCA1 variants by transcriptional activation and homologous recombination repair assays.BMC cancer · 2023Article
- Functional Analyses of Rare Germline MissenseGenes · 2023Article
- A dual-reporter system for investigating and optimizing protein translation and folding in E. coli.Nature communications · 2021Article
- Analysis and Interpretation of the Impact of Missense Variants in Cancer.International journal of molecular sciences · 2021Review
- Clinicopathological Features of Patients with the BRCA1 c.5339T>C (p.Leu1780Pro) Variant.Cancer research and treatment · 2020Article
- In silico analysis for determining the deleterious nonsynonymous single nucleotide polymorphisms ofMolecular biology research communications · 2019Article
- Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes.International journal of molecular sciences · 2017Article
- Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.Nature structural & molecular biology · 2016Article
- Beyond DNA: An Integrated and Functional Approach for Classifying Germline Variants in Breast Cancer Genes.International journal of breast cancer · 2016Review
- Effect of BET Missense Mutations on Bromodomain Function, Inhibitor Binding and Stability.PloS one · 2016Article
- Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic.Breast cancer research and treatment · 2015Article
- Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.PloS one · 2014Article
- Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.Cancer discovery · 2013Article
- Article
- BRCA1-directed, enhanced and aberrant homologous recombination: mechanism and potential treatment strategies.Cell cycle (Georgetown, Tex.) · 2012Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Carriers of germ line mutations in breast cancer susceptibility gene BRCA1 have an increased risk of developing breast and ovarian cancers; missense mutations have, however, been difficult to assess for disease association. Here we have used a biophysical approach to classify these variants. We established an assay for measuring the thermodynamic stability of the BRCA1 BRCT domains and investigated the effects of 36 missense mutations. The mutations show a range of effects. Some do not change the stability, whereas others destabilize the protein by as much as 6 kcal mol(-1); one-third of the mutants could not be expressed in soluble form in Escherichia coli, and we conclude that these destabilize the protein by an even greater amount. We tested several computer algorithms for their ability to predict the mutant effects and found that by grouping them into two classes (destabilizing by less than or more than 2.2 kcal mol(-1)), the algorithms could predict the stability changes. Importantly, with the exception of the few mutants located in the binding site, none showed a significant reduction in affinity for phosphorylated substrate. These results indicate that despite very large losses in stability, the integrity of the structure is not compromised by the mutations. Thus, the majority of mutations cause loss of function by reducing the proportion of BRCA1 molecules that are in the folded state and increasing the proportion of molecules that are unfolded. Consequently, small molecule stabilization of the structure could be a generally applicable preventative therapeutic strategy for rescuing many BRCA1 mutations.
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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.