Abstract
Functional impact of missense variants in BRCA1 predicted by supervised learning
Highlights
The BRCA1 gene encodes a large multifunction protein involved in cell-cycle and centrosome control, transcriptional regulation, and in the DNA damage response [1,2,3]
A significant number of breast and ovarian cancers are due to inherited mutations in the BRCA1 and BRCA2 genes
These variants were classified by sequence-analysis methods based on evolutionarily allowed amino acid residues: Align Grantham Variation Grantham Deviation (Align-GVGD) [18], Sorting Intolerant from Tolerant (SIFT) [19], Ancestral Sequence [9,11], and empirically derived rules encoded in a decision tree (Rule-based decision tree) [7]
Summary
The BRCA1 gene encodes a large multifunction protein involved in cell-cycle and centrosome control, transcriptional regulation, and in the DNA damage response [1,2,3]. Inherited mutations in this gene have been associated with an increased lifetime risk of breast and ovarian cancer (6–8 times that of the general population) [4]. There are several thousand known deleterious BRCA1 mutations that result in frameshifts and/or premature stop codons, producing a truncated protein product [5]. The functional impact of most missense variants that result in a single amino acid residue change in BRCA1 protein is not known. As genetic testing for inherited disease predispositions becomes more commonplace, predicting the clinical significance of missense variants and other UCVs will be increasingly important for risk assessment
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