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Novel BRCA1 splice-site mutation in ovarian cancer patients of Slavic origin

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Abstract

Mutations in breast cancer susceptibility gene 1 (BRCA1) lead to defects in a number of cellular pathways including DNA damage repair and transcriptional regulation, resulting in the elevated genome instability and predisposing to breast and ovarian cancers. We report a novel mutation LRG_292t1:c.4356delA,p.(Ala1453Glnfs*3) in the 12th exon of BRCA1, in the splice site region near the donor site of intron 12. It is a frameshift mutation with the termination codon generated on the third amino acid position from the site of deletion. Human Splice Finder 3.0 and MutationTaster have assessed this variation as disease causing, based on the alteration of splicing, creation of premature stop codon and other potential alterations initiated by nucleotide deletion. Among the most important alterations are frameshift and splice site changes (score of the newly created donor splice site: 0.82). c.4356delA was associated with two ovarian cancer cases in two families of Slavic origin. It was detected by next generation sequencing, and confirmed with Sanger sequencing in both cases. Because of the fact that it changes the reading frame of the protein, novel mutation c.4356delA p.(Ala1453Glnfs*3) in BRCA1 gene might be of clinical significance for hereditary ovarian cancer. Further functional as well as segregation analyses within the families are necessary for appropriate clinical classification of this variant. Since it has been detected in two ovarian cancer patients of Slavic origin, it is worth investigating founder effect of this mutation in Slavic populations.

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Author notes

  1. Ana Krivokuca and Vita Setrajcic Dragos have contributed equally the paper.

Authors and Affiliations

  1. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia

    Ana Krivokuca, Ljiljana Stamatovic, Ivana Boljevic, Jelena Rakobradovic & Mirjana Brankovic Magic

  2. Institute of Oncology Ljubljana, Zaloska cesta 2, 1 000, Ljubljana, Slovenia

    Vita Setrajcic Dragos, Ana Blatnik, Vida Stegel, Petra Skerl, Mateja Krajc & Srdjan Novakovic

  3. Military Medical Academy, Crnotravska 17, 11 000, Belgrade, Serbia

    Stevo Jovandic

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  1. Ana Krivokuca
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  2. Vita Setrajcic Dragos
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  3. Ljiljana Stamatovic
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Correspondence to Mirjana Brankovic Magic or Srdjan Novakovic.

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Krivokuca, A., Dragos, V.S., Stamatovic, L. et al. Novel BRCA1 splice-site mutation in ovarian cancer patients of Slavic origin. Familial Cancer 17, 179–185 (2018). https://doi.org/10.1007/s10689-017-0022-x

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  • DOI: https://doi.org/10.1007/s10689-017-0022-x

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