BRCA1 functional truth set, binary in silico calls (Cubuk et al. 2021)
Positive likelihood ratio, likelihood ratio for benignity and false-negative count for 70 tool-threshold combinations and 14 concordance combinations against the BRCA1 functional truth set.
Overview
Positive likelihood ratio, likelihood ratio for benignity and false-negative count for 70 tool-threshold combinations and 14 concordance combinations against the BRCA1 functional truth set.
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84 recorded evaluations, 247 metric rows. A comparison chart has not yet been validated for these results. The table retains the individual findings and their sources.
Results
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All evaluations
84 evaluations · 247 results. Different protocols are not a single leaderboard.
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Applied filters: All linked evaluations
Source checking is not independent reproduction. Release 2026-10-10-84341e0b121f.
Methods and evaluation design
Procedure, tasks and evaluated configurations
Recorded evaluations
Each evaluation records what was tested and under which conditions.
- alignGVGD_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- alignGVGD_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- BayesDEL_MaxAF_genespecific on the BRCA1 functional truth set (Cubuk et al. 2021)
- BayesDEL_MaxAF_universal on the BRCA1 functional truth set (Cubuk et al. 2021)
- BayesDEL_NoMaxAF_genespecific on the BRCA1 functional truth set (Cubuk et al. 2021)
- BayesDEL_NoMaxAF_universal on the BRCA1 functional truth set (Cubuk et al. 2021)
- CADD_phred_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- CADD_phred_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- CHASM on the BRCA1 functional truth set (Cubuk et al. 2021)
- ClinPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- Combined-PANTHER-AND-MetaSNP on the BRCA1 functional truth set (Cubuk et al. 2021)
- Combined-PMut-AND-rfPred on the BRCA1 functional truth set (Cubuk et al. 2021)
Baseline coverage
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- External evaluations
- 84
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Null control
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Protocol coverage CSV (gzip) · Model evaluation matrix (gzip) · Source table (gzip) · Release and checksums (gzip)
Coverage is derived from release 2026-10-10-84341e0b121f. Source citations describe the original records; they do not validate an unreviewed baseline proposal. No results have been generated by this audit.
Run instructions
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Strengths, limitations and unresolved questions
Evidence
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Evidence table
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Sources and history
Release 2026-10-10-84341e0b121f · Record review: source checked
2 source records and release history
- Clinical likelihood ratios and balanced accuracy for 44 in silico tools against multiple large-scale functional assays of cancer susceptibility genes · Original source · Genetics in Medicine 23(11):2096, published 2021-07-06; PMC8553612 full-text XML
- Cubuk et al. 2021, Supplementary tables 1-13 (41436_2021_1265_MOESM3_ESM.xlsx) · Original source · 41436_2021_1265_MOESM3_ESM.xlsx
Technical metadata and extraction receipts
Stable ID: brca-20261009-protocol-cubuk2021-brca1
- areas
- dna-genomes
- contexts
- clinical_research
- protocol
- Each tool's score is dichotomised at the Supplementary Table 5 threshold into deleterious or tolerated and compared with the BRCA1 functional class (HAP1 functional score above -0.748 tolerated, below -1.328 deleterious; intermediate scores excluded). Likelihood ratios follow Supplementary Table 7.
- version
- Supplementary Tables 6 and 9
- metric
- likelihood-ratio
- limitations
- Functional assay classes are the truth labels, used as proxies for pathogenic and benign; this is not a clinical classification endpoint.; Each tool-threshold combination is a binary call; tools with an intermediate band, and the tool combinations, leave the discordant or intermediate variants out of the counts, so denominators differ between rows (Supplementary Table 6 total_all).; Several tools were trained on ClinVar or HGMD variants, which may include assayed BRCA1/BRCA2 variants; Align-GVGD was trained on BRCA1/2 classifications (Discussion).; Thresholds are the published or commonly used cut-offs in Supplementary Table 5. The BayesDel 'gene-specific' rows use Cubuk et al.'s own thresholds, not the ENIGMA VCEP thresholds used in the existing judgements and in Ramadane-Morchadi et al. 2025.; The source's 'negative likelihood ratio' is TNR/FNR (Supplementary Table 7), stored as benignity-likelihood-ratio, the reciprocal of the conventional negative likelihood ratio. Its printed intervals disagree with the counts in 166 of 168 BRCA1/BRCA2 cells (in 131 they have the width of the row's positive likelihood ratio interval), so they are not recorded as uncertainty; the point values agree.; Where the cell a ratio divides by is zero in Supplementary Table 6, the printed ratio rests only on a zero-cell correction that the Table 9 note says was not applied; those results are disputed and not shown. Other zero-count rows are kept with a note.; Positive likelihood ratio intervals agree with the counts; their level is not printed (95% log-scale reproduces them).; Score versions are given only as the score source (ANNOVAR dbNSFP release or web server, Supplementary Table 5); web servers may have changed since.; The concordance combinations drop discordant variants, so their apparent gains come partly from excluding difficult variants (Discussion).; BRCA1 variants come from the RING and BRCT domains only.; The BRCA1 truth set is the Findlay et al. 2018 saturation genome editing data, which Ramadane-Morchadi et al. 2025 also use; agreement between these two studies is not independent replication. The ENIGMA BayesDel calibration in the existing judgements also uses functional reference labels in these domains; whether they include the same data is not established.
- denominator
- 1641
- source locator
- Supplementary Tables 2, 3, 5, 6, 7 and 9 (BRCA1 columns); Methods 'Statistical analysis'
Related records
- uses data: BRCA1 functional truth set: 1641 missense variants classed deleterious or tolerated by HAP1 cell survival after saturation genome editing
- assessment: alignGVGD_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: alignGVGD_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: BayesDEL_MaxAF_genespecific on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: BayesDEL_MaxAF_universal on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: BayesDEL_NoMaxAF_genespecific on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: BayesDEL_NoMaxAF_universal on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: CADD_phred_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: CADD_phred_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: CHASM on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: ClinPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-PANTHER-AND-MetaSNP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-PMut-AND-rfPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Polyphen2_HVAR-AND-SIFT-AND-MutationTaster on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-alignGVGD_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-Eigen-PC_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-MetaSNP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-MutationTaster on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-MutPred_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-PANTHER on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-PMut-AND-rfPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-PMut on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-Polyphen2_HVAR on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-rfPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Combined-Revel_b-AND-VEST3_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Condel on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: DANN_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: DANN_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: DANN_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Eigen-PC_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Eigen-PC_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: FATHMM on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: fathmm-MKL_coding on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Gavin on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: GenoCanyon on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: GERP++_RS_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: GERP++_RS_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: GERP++_RS_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Grantham_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Grantham_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Integrated_fitCons_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: LRT on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: M-CAP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MetaLR on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MetaSNP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MetaSVM on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MLP_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MLP_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MLP_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MSC-CADD-based on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MSC-PolyPhen2-based on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MSC-SIFT-based on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MutationAssessor on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MutationTaster on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MutPred_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MutPred_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MutPred_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: MVP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PANTHER on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: phastCons100way_vertebrate on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: phastCons20way_mammalian on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PhD-SNPg-all on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PhD-SNPg-p005 on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: phyloP100way_vertebrate on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: phyloP20way_mammalian on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PMut on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Polyphen2_HDIV on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Polyphen2_HVAR on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PON-P2 on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PredictSNP on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: primateAI_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: primateAI_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: PROVEAN on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Revel_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Revel_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: Revel_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: rfPred on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: SIFT on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: SiPhy_29way_logOdds on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: SNAP2 on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: SuSPect on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: VEST3_a on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: VEST3_b on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: VEST3_c on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessment: VEST4 on the BRCA1 functional truth set (Cubuk et al. 2021)
- assessed by: Interpret BRCA1/BRCA2 germline variants