Illustration from Scientific Research

The Missense pathogenic variants track displays all BRCA1 missense changes (N= 38) classified as pathogenic by the ClinGen ENIGMA BRCA1/2 VCEP (last consulted August 22, 2024) (scale not preserved). Note that pathogenic missense variants cluster at the RING and BRCT domains, with no pathogenic missense variants reported so far in other regions. The PP3/BP4/BP1 track summarizes ClinGen ENIGMA BRCA1/2 VCEP rules to apply ACMG/AMP predictive evidence to BRCA1 missense changes. Depending on BayesDel-noAF scores, PP3 (>=0.28) or BP4 (<=0.15) computational evidence is applied to missense variants targeting the RING, CC, or BRCT domains. By contrast, PP3/BP4 is not applied to missense variants targeting other regions (mostly, disordered regions). Instead, the BP1_Strong code is applied (regardless of computational predictions). The Domains/Motifs cartoon track represents BRCA1 conserved domains/motifs as defined by the ClinGen ENIGMA BRCA1/2 VCEP, with the RING and BRCT domains defined as clinically important functional domains and the CC (coiled-coil) motif as potentially clinically important (note that the precise boundaries of these domains might be slightly different according to other sources such as UniProt:P38398). The Key partners track shows BRCA1 key interacting proteins BARD1 (interacting with the RING domain), PALB2 (interacting with the CC motif), Abraxas, BRIP1 (also known as BACH1), and CtIP (the latter three interacting with the BRCT domains). The AlphaFold-disorder cartoon track represents BRCA1 disordered regions as deduced from the AlphaFold-2 model AF-P38398-F1 (p.LDDT score <70). The AlphaFold2-models track displays the BRCA1/BARD1 RING heterodimer and BRCT-domain AlphaFold2 models generated for this study. The PDBs track shows ID, descriptive name, and method for experimentally determined 3D structures used in this study.

DOI