Functional redundancy of exon 12 of<i>BRCA2</i>revealed by a comprehensive analysis of the c.6853A>G (p.I2285V) variant
Bibliographic record
Abstract
Variants of unknown significance (VUS) in BRCA1 and BRCA2 are common, and present significant challenges for genetic counseling. We observed that BRCA2: c.6853A>G (p.I2285V) (Breast Cancer Information Core [BIC] name: 7081A>G; http://research.nhgri.nih.gov/bic/) co-occurs in trans with the founder mutation c.5946delT (p.S1982RfsX22) (BIC name: 6174delT), supporting the published classification of p.I2285V as a neutral variant. However, we also noted that when compared with wild-type BRCA2, p.I2285V resulted in increased exclusion of exon 12. Functional assay using allelic complementation in Brca2-null mouse embryonic stem cells revealed that p.I2285V, an allele with exon 12 deleted and wild-type BRCA2 were all phenotypically indistinguishable, as measured by sensitivity to DNA-damaging agents, effect on irradiation-induced Rad51 foci formation, homologous recombination, and overall genomic integrity. An allele frequency study showed the p.I2285V variant was identified in 15 out of 722 (2.1%) Ashkenazi Jewish cases and 10 out of 475 (2.1%) ethnically-matched controls (odds ratio, 0.99; 95% confidence interval: 0.44-2.21; P=0.97). Thus the p.I2285V variant is not associated with an increased risk for breast cancer. Taken together, our clinical and functional studies strongly suggest that exon 12 is functionally redundant and therefore missense variants in this exon are likely to be neutral. Such comprehensive functional studies will be important adjuncts to genetic studies of variants.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".