Probing structure-function relationships in missense variants in the carboxy-terminal region of BRCA1.
Germline inactivating variants in BRCA1 lead to a significantly increased risk of breast and ovarian cancers in carriers. While the functional effect of many variants can be inferred from the DNA sequence, determining the effect of missense variants present a significant challenge. A series of biochemical and cell biological assays have been successfully used to explore the impact of these variants on the function of BRCA1, which contribute to assessing their likelihood of pathogenicity. It has been determined that variants that co-localize with structural or functional motifs are more likely to disrupt the stability and function of BRCA1. Here we assess the functional impact of 37 variants chosen to probe the functional impact of variants in phosphorylation sites and in the BRCT domains. In addition, we perform a meta-analysis of 170 unique variants tested by the transcription activation assays in the carboxy-terminal domain of BRCA1 using a recently developed computation model to provide assessment for functional impact and their likelihood of pathogenicity.
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America; Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
Renato S
RS
Carvalho
Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
Renata B V
RB
Abreu
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America.
Aneliya
A
Velkova
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America.
Sylvia
S
Marsillac
Universidade Federal de Alagoas, Maceió, AL, Brazil.
Renato S
RS
Rodarte
Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
Guilherme
G
Suarez-Kurtz
Department of Statistical Science, Duke University, Durham, North Carolina, United States of America.
Edwin S
ES
Iversen
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America.
Alvaro N A
AN
Monteiro
Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Marcelo A
MA
Carvalho
D000483:Alleles; D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001499:Bayes Theorem; D017124:Conserved Sequence; D006801:Humans; D020125:Mutation, Missense; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D019313:BRCA1 Protein