Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.
Pires, Douglas EV
Ascher, David B
Springer Science and Business Media LLC
MetadataShow full item record
Aljarf, R., Shen, M., Pires, D. E., & Ascher, D. B. (2022). Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.. Sci Rep, 12 (1) https://doi.org/10.1038/s41598-022-13508-3
Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265
Funder: National Health and Medical Research Council; doi: http://dx.doi.org/10.13039/501100000925
Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100010269
BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanism. DNA repair defects caused by BRCA1 and BRCA2 missense variants increase the risk of developing breast and ovarian cancers. Accurate identification of these variants becomes clinically relevant, as means to guide personalized patient management and early detection. Next-generation sequencing efforts have significantly increased data availability but also the discovery of variants of uncertain significance that need interpretation. Experimental approaches used to measure the molecular consequences of these variants, however, are usually costly and time-consuming. Therefore, computational tools have emerged as faster alternatives for assisting in the interpretation of the clinical significance of newly discovered variants. To better understand and predict variant pathogenicity in BRCA1 and BRCA2, various machine learning algorithms have been proposed, however presented limited performance. Here we present BRCA1 and BRCA2 gene-specific models and a generic model for quantifying the functional impacts of single-point missense variants in these genes. Across tenfold cross-validation, our final models achieved a Matthew's Correlation Coefficient (MCC) of up to 0.98 and comparable performance of up to 0.89 across independent, non-redundant blind tests, outperforming alternative approaches. We believe our predictive tool will be a valuable resource for providing insights into understanding and interpreting the functional consequences of missense variants in these genes and as a tool for guiding the interpretation of newly discovered variants and prioritizing mutations for experimental validation.
BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Genes, BRCA2, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Missense, Ovarian Neoplasms
External DOI: https://doi.org/10.1038/s41598-022-13508-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338479
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: firstname.lastname@example.org