Assessing the Clinical Relevance of BRCA1 RING Domain Variants of Uncertain Significance.
Simple Summary: Women who inherit harmful variants in the BRCA1 tumour suppressor gene have an elevated risk of developing multiple cancers, and may benefit from increased screening and preventative surgeries. Unfortunately, ~40% of BRCA1 variants have an unknown effect on cancer risk, leaving their...
| Published in: | Current Oncology Vol. 33; no. 7; pp. 399 - 424 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Published: |
MDPI
Jul2026
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=195807431&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 195807431 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 11980052 5EKK jtl: Current Oncology issn: 11980052 maglogo: N pubinfo: dt: Jul2026 vid: 33 iid: 7 pid: 97109 pub: MDPI artinfo: ui: 195807431 10.3390/curroncol33070399 195807431 ppf: 399 ppct: 25 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Assessing the Clinical Relevance of BRCA1 RING Domain Variants of Uncertain Significance. aug: au: Martin, Matthew D. Torretto, Gabriella C. Islam, Kaamraan Archer, Nicole E. Feilotter, Harriet E. Davey, Scott K. affil: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada sug: ab: Simple Summary: Women who inherit harmful variants in the BRCA1 tumour suppressor gene have an elevated risk of developing multiple cancers, and may benefit from increased screening and preventative surgeries. Unfortunately, ~40% of BRCA1 variants have an unknown effect on cancer risk, leaving their carriers with inconclusive information to guide care decisions. This study provides evidence for the classification of variant effects within BRCA1's RING region using two complementary approaches: (1) an artificial intelligence algorithm designed to predict the severity of variant impacts, and (2) a cell-based assay that evaluates whether variant BRCA1 RING proteins retain an interaction required for normal functioning. The results were generally consistent, and confidently clarified the effect of four variants on cancer risk. This study both aids the preventative care decisions for carriers of these variants and underscores the potential of protein-specific approaches for variant characterization. The BRCA1 protein serves an essential function in maintaining genomic integrity, to the extent that up to 80% of women carrying a pathogenic BRCA1 variant develop breast cancer (BC). Most of these carriers would benefit from prophylactic care, but genetic screens that uncover variants of uncertain significance (VUSs) do not provide insight on disease risk or clinical decision-making. In accordance with guidelines established by The American College of Molecular Genetics (ACMG) and Association for Molecular Pathology (AMP), this study produced computational and functional evidence to inform the reclassification of BRCA1 VUSs as pathogenic or benign, with a specific focus on the abundant subset of missense variants within the RING domain. A six-feature linear support vector machine (LSVM) specifically trained on BRCA1 RING variants performed well (84% accurate in predicting in vitro binding loss) and provided supporting classification evidence for 322 VUS. A mammalian cell co-immunoprecipitation (co-IP) assay that quantified the binding between variant BRCA RING constructs and endogenous BARD1 provided corroborating strong evidence for nine VUSs and correlated with a homology-directed repair (HDR) assay by Starita et al. (p = 0.04). The combined evidence warrants the reclassification of three VUSs as likely benign (N16S, A17D, and E100D) and one as likely pathogenic (H41P), and underscores the promise of domain-specific approaches for missense VUS reclassification. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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