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Abstract
Germline inactivating mutations in BRCA1 and BRCA2 genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS). Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS). Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V) located in the C-terminal region of BRCA1 by combining in silico prediction tools and structural analysis with a transcription activation (TA) assay. The in silico prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V) reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic BRCA1 mutations.
Highlights
Between 10 and 20% of the breast cancer cases appearing in the general population present familial history of the disease [1]
Classification of genetic variants as pathogenic is challenging, for missense changes and for silent or intronic variants that cannot be directly associated with increased cancer risk and are classified as variants of uncertain significance (VUS), which are found in 13% of BRCA1 and BRCA2 genetic tests [5]
Our results indicate that three of them (Y1703S, W1718L, G1770V) have significant functional impact and may represent pathogenic BRCA1 variants while the remaining four do not have a functional impact
Summary
Between 10 and 20% of the breast cancer cases appearing in the general population present familial history of the disease [1]. Diverse multifactorial likelihood algorithms have been developed and applied for both BRCA1 and BRCA2 variants (reviewed in Spurdle et al, 2011) [6] These models use the combination of a number of independent features (sequence conservation, type of amino-acid change, familial cosegregation, family and personal cancer history, tumor data, cooccurrence with a deleterious mutation, and severity of amino acid change) to establish the likelihood that a given VUS is pathogenic or non-pathogenic. In the work presented here, we combine a functional assay - the transcription activation (TA) assay, which is based on the function of the BRCA1 carboxy-terminal region (aa 1396–1863) in transcriptional activation domain when linked to a sequence-specific DNA binding module - [10] with protein structural analyses [11] to assess the functional impact of seven BRCA1 C-terminal VUS. Our results indicate that three of them (Y1703S, W1718L, G1770V) have significant functional impact and may represent pathogenic BRCA1 variants while the remaining four do not have a functional impact
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