loading round

round · round_1747403330

BRCA1

NM_007294.4:c.181T>G · p.Cys61Gly · chr17:43106487 T>G

missense_varianteasytruth · Pathogenic

Evidence shown to the agents

identical pack · five strategies

gnomAD

AF popmax —
AC 0/1450000 · hom 0

In-silico

REVEL 0.957 · CADD 27.4
AlphaMissense 0.984 · SpliceAI 0.02

Functional

loss_of_function (score -2.1)

Reasoning traces

five verdicts · identical evidence

Strict Rule

strict_rule

predicted Ptruth P

Pathogenic ↔ Pathogenic

matches expert consensus

Applied criteria

PS3PM2PP3PM1

Reasoning

PS3 applies (Findlay 2018 saturation editing shows loss of function). PM2 applies (absent from gnomAD). PP3 applies (REVEL 0.957, CADD 27.4, AlphaMissense 0.984 — three computational lines converge). PM1 applies (RING domain hotspot). Combining: 1 PS + 2 PM + 1 PP -> Pathogenic.

composite score0.963

accuracy1.00

criterion match0.75

self-reported confidence: 92%

Functional First

functional_first

predicted Ptruth P

Pathogenic ↔ Pathogenicmatches expert consensus

Applied criteria

PS3PM2PP3

Reasoning

Functional evidence is decisive here: Findlay 2018 SGE assay scores this variant at -2.1, well within loss-of-function range. PS3 alone leans LP at minimum. Combined with PM2 (absent from gnomAD) and PP3 (high-quality predictor consensus), the call is Pathogenic.

composite score1.000

accuracy1.00

criterion match1.00

self-reported confidence: 94%

In-Silico First

insilico_first

predicted Ptruth P

Pathogenic ↔ Pathogenicmatches expert consensus

Applied criteria

PP3_strongPS3PM2

Reasoning

All three modern predictors converge strongly on damaging (AlphaMissense 0.984, REVEL 0.957, CADD 27.4). I upgrade PP3 to moderate per my strategy. PS3 from functional data and PM2 from absence in gnomAD reinforce. Pathogenic.

composite score0.950

accuracy1.00

criterion match0.67

self-reported confidence: 95%

Population First

population_first

predicted LPtruth P

Likely Pathogenic ↔ Pathogenicdelta vs truth

Applied criteria

PM2PP3PS3

Reasoning

Variant is absent from gnomAD v4 — PM2 applies with strong weight in a well-established disease gene. Functional and computational evidence support pathogenicity. Without segregation or case-control data, I land at Likely Pathogenic rather than full Pathogenic.

composite score0.850

accuracy0.75

criterion match1.00

self-reported confidence: 81%

Conservative

conservative

predicted LPtruth P

Likely Pathogenic ↔ Pathogenicdelta vs truth

Applied criteria

PS3PM2

Reasoning

I require multiple PS-level lines for Pathogenic. Here I have PS3 (functional) + PM2 (absent from gnomAD), which clears Likely Pathogenic but not full Pathogenic without segregation or independent case data. Likely Pathogenic.

composite score0.850

accuracy0.75

criterion match1.00

self-reported confidence: 78%