Multimodal Approach to Characterize Missense Mutation Identified in h-BRCA2
Bibliographic record
Abstract
Correspondence to: avarma@actrec.gov.in Background: BRCA2 protein plays an essential role in homologous recombination. Germ-line mutations in BRCA2 confer an increased risk of breast cancer. Many missense mutations have been identified in BRCA2; however, most of them are classified as variants of “Uncertain Significance” due to a lack of structural, functional, and clinical studies. Materials and Methods: Here, multidisciplinary in silico, in vitro and biophysical approaches have been explored to characterize an unclassified missense mutation, BRCA2 Arg2502Cys, identified from a case-control study. Wild-type and mutant proteins were overexpressed and purified using bacterial expression system. Comparative secondary and tertiary studies were performed using circular dichroism and fluorescence spectroscopy. Results: Circular-dichroism and Fluorescence spectroscopy showed that the Arg2502Cys mutation in hBRCA2 (residues 2350-2545) decreases the α-helical/β-sheet propensity of the wild-type protein and perturb the tertiary structure conformation. In molecular dynamics simulation studies, the mutation perturbs the structural integrity and conformational dynamics by altering the intramolecular H-bonds, overall compactness and stability of the hydrophobic core. Principal component analysis indicated that Arg2502Cys mutant exhibits comparatively large conformational transitions and periodic fluctuation conformers throughout the 250ns trajectories. Conclusion: Therefore, to our conclusion, BRCA2 Arg2502Cys mutation perturbed the structural integrity and conformational dynamics of BRCA2 which in turn may affect the function of the protein and could result in cancer predisposition. Publication History Article published online: 22 August 2022 © 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".