title: Collective evidence supports neutrality of BRCA1 V1687I, a novel sequence variant in the conserved THV motif of the first BRCT repeat.
abstract: Unambiguous classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) is a challenging task that vexes health care providers and has profound implications for patients and their family members. Numerous VUS have been described to date, which await assessment of their functional, hence clinical, impact. As a result of a routine BRCA1/BRCA2 mutational screening, we identified a previously unreported BRCA1 sequence alteration [c.5178G>A (V1687I)] in a patient diagnosed with early onset triple negative breast cancer. The sequence alteration falls in the invariant THV motif of the BRCT domain. To investigate its significance, we applied an integrated approach that, in addition to genetic and histopathological data, included in silico analyses, comparative structural modeling and verification of BRCT-mediated interactions. In line with web-based algorithms that predicted the benign nature of BRCA1 V1687I, the three-dimensional model of the BRCA1 V1687I BRCT domain did not reveal any major structural changes relative to its wild-type counterpart, thus suggesting that BRCA1 V1687I has a negligible impact on both the local architecture and the overall stability of the protein. Consistently, the BRCA1 V1687I protein was properly expressed and localized to the nucleus, and it was still capable of binding three BRCT-interacting, DNA damage response, and repair partner proteins, namely BRIP1/FANCJ, CtIP, and Abraxas. Our collected evidence suggests that, although occurring in a highly conserved region, the BRCA1 V1687I variant is likely a benign sequence alteration.
authors.affiliation: Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, via del Pozzo 71, 41100, Modena, Italy. hbc@unimo.it
authors.forename: Laura
authors.initials: L
authors.lastname: Cortesi
authors.forename: Arcangela
authors.initials: A
authors.lastname: De Nicolo
authors.forename: Veronica
authors.initials: V
authors.lastname: Medici
authors.forename: Marco
authors.initials: M
authors.lastname: Marino
authors.forename: Daniela
authors.initials: D
authors.lastname: Turchetti
authors.forename: Laura Maria
authors.initials: LM
authors.lastname: Pradella
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.forename: Emilio
authors.initials: E
authors.lastname: Parisini
authors.forename: Massimo
authors.initials: M
authors.lastname: Federico
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005260:Female; D024522:Genes, BRCA2; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human