What does BRCA1 actually mean?
A thread through the evidence — ClinVar, gnomAD, ClinGen, and GTEx.
Variation
BRCA1 has 15,670 variants submitted to ClinVar. Among them, 14936 are classified as pathogenic or likely pathogenic, and 7,709 remain Variants of Uncertain Significance. Each variant is a thread in the story — some we understand, many we're still learning.
Interpretation
Here's the uncomfortable truth: 49% of BRCA1 variants in ClinVar are classified as "Uncertain Significance" (VUS). That means the labs that sequenced them couldn't confidently say whether they're harmful or harmless. This isn't a failure — it's an honest reflection of where the science stands. Interpretations change as evidence accumulates. And 38 variants have conflicting classifications across submitters — labs sometimes disagree on what the evidence means.
Constraint
gnomAD's constraint metrics tell us how tolerant BRCA1 is to different types of mutations in the general population. A LOEUF score of 0.89 suggests moderate tolerance. This is indirect evidence, but it's powerful: evolution has been running this experiment for millions of years.
Meaning
So what does it all mean? BRCA1 is a gene we're still learning about. 14936 variants are classified as pathogenic or likely pathogenic — evidence that's strong and actionable when it applies to you. 7709 variants remain uncertain. That's the honest state of genomic medicine: if you carry a pathogenic BRCA1 variant, the evidence speaks clearly. If you carry a VUS, the evidence is still accumulating. Either way, you deserve to understand what the science actually says.