Background:BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast–ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk.
Objective: To investigate a panel of missense variants.
Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated.
Conclusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.
- DBD, DNA binding domain
- tumour suppressor
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In our paper "Classification of BRCA1 variants of unknown clinical significance" we reported that BRCA1 variant M1628V presented markedly reduced activity which suggested that it represented a deleterious variant. During the course of additional experiments (Carvalho and Monteiro, unpublished data) we noticed that constructs containing the M1628V variant described in our paper also included a 3' mutation leading to a truncated protein that was overlooked. We have now generated correct constructs for this variant and performed extensive testing. Contrary to what was reported this variant displayed activity comparable to the wild type BRCA1 suggesting that it corresponds to a neutral variant. We regret this error and apologize for any confusion or inconvenience it may have caused.
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