Collective evidence supports neutrality of BRCA1 V1687I, a novel sequence variant in the conserved THV motif of the first BRCT repeat

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.