Assessing the Clinical Relevance of Brca1-ring Domain Variants of Uncertain Significance
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Authors
Martin, Matthew David
Date
2025-09-25
Type
thesis
Language
eng
Keyword
BRCA1 , Cancer , Breast , Ovarian , Tumor Supressor , VUS
Alternative Title
Abstract
BRCA1 serves multiple genome integrity functions critical for suppressing tumor development. Women who inherit BRCA1 Variants of Uncertain Significance (VUS) face uncertainty about whether their variant is benign, or pathogenic and substantially increases their risk of breast and ovarian cancer. Considering that the N-terminal BRCA1-RING domain harbors over 500 missense VUS and appears essential to the critical function of the full protein, a domain-specific machine learning algorithm combined with a BARD1 co-immunoprecipitation assay was used to predict the functional impacts of variants. The computational and in vitro evidence warrants reclassification of two VUS as likely-benign (N16S, E100D) and two as likely-pathogenic (C27R, H41P), and one as pathogenic (C24G) which will improve preventative care decisions for carriers. Five more received evidence that shifts them towards a likely-pathogenic (L86R, I68T) and likely-benign (Q54P, C91R, K20Q) classification.
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Attribution-NonCommercial 4.0 International
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial 4.0 International