Functional significance of missense variants in BRCA1
Bibliographic record
Abstract
1314 BRCA1 is a tumor suppressor gene product involved in transcriptional regulation, DNA-damage repair, cell-cycle control and the maintenance of genomic integrity. Germ-line mutations in the BRCA1 gene predispose individuals to breast and ovarian cancer. Cancer-associated BRCA1 mutations abolish its transcriptional activity, indicating that this activity is crucial for the maintenance of the normal phenotype. Development of cancer requires the loss of the wild type allele, since the inherited mutation predisposing allele is recessive. A substantial number of BRCA1 germ-line mutations encode for missense variants. Classification and predictive risk assessment are difficult due to a lack of information about their impact on the BRCA1 tumor suppressor function. Classification of missense variants into cancer-predisposing mutations or benign polymorphisms is crucial for identifying individuals at risk. In this study, we have investigated 13 missense variants for their ability to activate transcription in both yeast and mammalian transcriptional assays. Five variants (H1402Y, H1421Y, S1512I, M1628T, T1720A) were able to activate transcription comparably to the wild-type BRCA1 and are likely to be benign polymorphisms. Eight variants (L1407P, M1628V, T1685I, G1706A, A1752P, G1788V, V1809F and W1837R) showed significantly reduced ability to activate transcription similar to the known deleterious controls and likely represent cancer-associated variants. This study contributes to a better understanding of BRCA1 unclassified variants and has important implications for carriers of these mutations.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".