ArticleEuropean journal of human genetics : EJHG2008
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.
Article in European journal of human genetics : EJHG, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- Computational approaches for predicting variant impact: An overview from resources, principles to applications.Frontiers in genetics · 2022Review
- One-Pot Surface Modification of β-CuACS omega · 2021Article
- LAHMA: structure analysis through local annotation of homology-matched amino acids.Acta crystallographica. Section D, Structural biology · 2021Article
- Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort.BMC medical genetics · 2019Article
- Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance.Human genomics · 2018Article
- A comparison of cosegregation analysis methods for the clinical setting.Familial cancer · 2018Article
- BRCA1 Circos: a visualisation resource for functional analysis of missense variants.Journal of medical genetics · 2015Article
- Prognostic value of CtIP/RBBP8 expression in breast cancer.Cancer medicine · 2013Article
- Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs.Human mutation · 2012Article
- Full-exon pyrosequencing screening of BRCA germline mutations in Mexican women with inherited breast and ovarian cancer.PloS one · 2012Article
- Quantitative copy number analysis by Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness.Breast cancer research : BCR · 2011Article
- On the role of electrostatics in protein-protein interactions.Physical biology · 2011Review
- Impact of BRCA1 BRCT domain missense substitutions on phosphopeptide recognition.Biochemistry · 2011Article
- Article
- Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.Cancer research · 2010Article
- Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.Nature reviews. Molecular cell biology · 2010Review
- Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.Mutation research · 2009Article
- Positional analyses of BRCA1-dependent expression in Saccharomyces cerevisiae.Cell cycle (Georgetown, Tex.) · 2008Article
- The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50.Biochemistry · 2008Article
- Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance.Human mutation · 2008Article
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Authors and funding
18 authors at 7 institutions in 5 countries.
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Abstract
A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.
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