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Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort

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Abstract

Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family. We investigated 32 variants previously detected in 33 samples from patients with a family history of breast or ovarian cancer. cDNA was analyzed for alternative transcripts and selected missense variants located in the BRCT domains of BRCA1 were assessed for their trans-activation ability. Although an extensive cDNA analysis was done, only three of the 32 variants appeared to affect the splice-process (BRCA1 c.213-5T>A, BRCA1 c.5434C>G and BRCA2 c.68-7T>A). In addition, two variants located in the BRCT domains of BRCA1 (c.5075A>C p.Asp1692Ala and c.5513T>G p.Val1838Gly) were shown to abolish the BRCT domain trans-activation ability, whereas BRCA1 c.5125G>A p.Gly1709Arg exhibited equal trans-activation capability as the WT domain. These functional studies may offer further insights into the pathogenicity of certain identified variants; however, this assay is only applicable for a subset of missense variants.

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Acknowledgments

We thank Alvaro N. A. Monteiro for kindly providing us with the BRCT containing plasmids necessary for the trans-activation assay. We also thank “Helse Nord” for providing the necessary funding for this study (Grant # SFP1161-14).

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Authors and Affiliations

  1. Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway

    Elisabeth Jarhelle, Hilde Monica Frostad Riise Stensland & Marijke Van Ghelue

  2. Department of Clinical Medicine, University of Tromsø, Tromsø, Norway

    Elisabeth Jarhelle & Marijke Van Ghelue

  3. Northern Norway Family Cancer Center, University Hospital of North Norway, Tromsø, Norway

    Hilde Monica Frostad Riise Stensland & Marijke Van Ghelue

  4. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Lovise Mæhle

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  1. Elisabeth Jarhelle
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  2. Hilde Monica Frostad Riise Stensland
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  4. Marijke Van Ghelue
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Correspondence to Marijke Van Ghelue.

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All participants gave written informed consent for diagnostic testing. The project was submitted to the appropriate regional ethics committee, however, since the samples were tested diagnostically the regional ethical committee waved the need for ethical approval based on the Norwegian regional health organization law § 2 and § 9 and the Norwegian research ethical law § 4.

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Jarhelle, E., Riise Stensland, H.M.F., Mæhle, L. et al. Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort. Familial Cancer 16, 1–16 (2017). https://doi.org/10.1007/s10689-016-9916-2

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