Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation.

Genetic testing for BRCA1, a DNA repair protein, can identify carriers of pathogenic variants associated with a substantially increased risk for breast and ovarian cancers. However, an association with increased risk is unclear for a large fraction of BRCA1 variants present in the human population. Most of these variants of uncertain clinical significance lead to amino acid changes in the BRCA1 protein. Functional assays are valuable tools to assess the potential pathogenicity of these variants. Here, we systematically probed the effects of substitutions in the C terminus of BRCA1: the N- and C-terminal borders of its tandem BRCT domain, the BRCT-[N-C] linker region, and the α1 and α'1 helices in BRCT-[N] and -[C]. Using a validated transcriptional assay based on a fusion of the GAL4 DNA-binding domain to the BRCA1 C terminus (amino acids 1396-1863), we assessed the functional impact of 99 missense variants of BRCA1. We include the data obtained for these 99 missense variants in a joint analysis to generate the likelihood of pathogenicity for 347 missense variants in BRCA1 using VarCall, a Bayesian integrative statistical model. The results from this analysis increase our understanding of BRCA1 regions less tolerant to changes, identify functional borders of structural domains, and predict the likelihood of pathogenicity for 98% of all BRCA1 missense variants in this region recorded in the population. This knowledge will be critical for improving risk assessment and clinical treatment of carriers of BRCA1 variants.

A meteorological dataset of the West African monsoon during the 2016 DACCIWA campaign.

As part of the Dynamics-Aerosol-Chemistry-Cloud Interactions in West Africa (DACCIWA) project, extensive in-situ measurements of the southern West African atmospheric boundary layer (ABL) have been performed at three supersites Kumasi (Ghana), Savè (Benin) and Ile-Ife (Nigeria) during the 2016 monsoon period (June and July). The measurements were designed to provide data for advancing our understanding of the relevant processes governing the formation, persistence and dissolution of nocturnal low-level stratus clouds and their influence on the daytime ABL in southern West Africa. An extensive low-level cloud deck often forms during the night and persists long into the following day strongly influencing the ABL diurnal cycle. Although the clouds are of a high significance for the regional climate, the dearth of observations in this region has hindered process understanding. Here, an overview of the measurements ranging from near-surface observations, cloud characteristics, aerosol and precipitation to the dynamics and thermodynamics in the ABL and above, and data processing is given. So-far achieved scientific findings, based on the dataset analyses, are briefly overviewed.