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

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• 作者：Elisabeth Jarhelle ; Hilde Monica Frostad Riise Stensland ; Lovise Mæhle…
• 关键词：BRCA1 ; BRCA2 ; Cancer ; cDNA ; analysis ; Functional ; assay
• 刊名：Familial Cancer
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：16
• 期：1
• 页码：1-16
• 全文大小：
• 刊物类别：Medicine
• 刊物主题：Cancer Research; Human Genetics; Epidemiology; Biomedicine, general;
• 出版者：Springer Netherlands
• ISSN：1573-7292
• 卷排序：16

文摘

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.