# Test every possible mutation in every cancer gene so no result is 'uncertain'

Source: https://onco.cc/ideas/idea-prev-vus-saturation-editing-consortium/  
OnCo record `idea-prev-vus-saturation-editing-consortium` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Genetic testing often returns a variant of uncertain significance that cannot be acted on, most often in people of non-European ancestry. Saturation genome editing has already classified nearly all BRCA1 single-nucleotide variants; a consortium doing the same for the roughly 30 actionable hereditary cancer genes would end most uncertain results.

## Summary

Patients often receive a genetic result of uncertain significance that cannot be acted on, so this idea forms a philanthropy-funded consortium to produce saturation genome editing functional maps for the roughly 30 actionable hereditary cancer genes and submit them to ClinVar. Saturation editing has already classified nearly all BRCA1 single-nucleotide variants, VUS rates are especially high in non-European populations, and functional evidence is now accepted in ACMG classification frameworks. The test funds five genes a year and tracks VUS reclassification rates in clinical laboratories. With preclinical evidence, it addresses the bottlenecks Inherited risk is mostly unidentified and Biomarkers are not validated or standardised, and links to CRISPR functional genomics, BRCA and TP53.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Complete functional maps resolve at least 80% of current variants of uncertain significance in hereditary cancer genes within five years.
- Rationale: VUS rates of 20-40% in non-European populations undermine testing, and functional evidence is now accepted by ACMG classification frameworks.
- Proposed test: Fund five genes per year and track VUS reclassification rates in clinical laboratories.
- Maturity: preclinical-evidence
- Actor: philanthropy

## Sources

- Bottleneck evidence (Inherited risk is mostly unidentified): Childers et al., National estimates of genetic testing in women with breast or ovarian cancer (JCO 2017): https://doi.org/10.1200/JCO.2017.73.6314

## Connected records

- collections: [ClinVar](https://onco.cc/collections/clinvar/)
- fronts: [Prevention & Risk](https://onco.cc/fronts/prevention/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [TP53](https://onco.cc/targets/tp53/)
- terms: [Variant of uncertain significance (VUS)](https://onco.cc/terms/vus/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Inherited risk is mostly unidentified](https://onco.cc/bottlenecks/b-hereditary-risk/)
- key papers: [National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer](https://onco.cc/key-papers/paper-childers-j-clin-oncol/)

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