title: Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.
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.
authors: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway.|Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
authors: Elisabeth
authors: E
authors: Jarhelle
authors: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway.|Northern Norway Family Cancer Center, University Hospital of North Norway, Tromsø, Norway.
authors: Hilde Monica Frostad
authors: HM
authors: Riise Stensland
authors: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors: Lovise
authors: L
authors: Mæhle
authors: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway. marijke.van.ghelue@unn.no.|Department of Clinical Medicine, University of Tromsø, Tromsø, Norway. marijke.van.ghelue@unn.no.|Northern Norway Family Cancer Center, University Hospital of North Norway, Tromsø, Norway. marijke.van.ghelue@unn.no.
authors: Marijke
authors: 0000-0002-8687-6374
authors: M
authors: Van Ghelue
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009664:Norway; D010051:Ovarian Neoplasms / Q000235:genetics*; D012326:RNA Splicing
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA1; BRCA2; Cancer; Functional-assay; cDNA-analysis