ArticleScience advances2022
Cancer-driving mutations are enriched in genic regions intolerant to germline variation.
Article in Science advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 10 citations in OpenAlex.
- Distinct mutational landscapes for germline and somatic cancer variants in forty tumor suppressor genes.American journal of human genetics · 2026Article
- Distinct mutational landscapes when comparing germline and somatic cancer variants in forty tumor suppressor genes.bioRxiv : the preprint server for biology · 2026Article
- MutAnt: mutation annotation tool predicts deleteriousness of missense mutations and improves mutation calling from transcriptomics.Human genetics · 2025Article
- Cancer-type somatic mutations in saccular cerebral aneurysms.European journal of human genetics : EJHG · 2025Article
- Functional Characterization of Variants of Unknown Significance of Fibroblast Growth Factor Receptors 1-4 and Comparison With AI Model-Based Prediction.JCO precision oncology · 2025Article
- Diverse ancestral representation improves genetic intolerance metrics.Nature communications · 2025Article
- Protein structural context of cancer mutations reveals molecular mechanisms and candidate driver genes.Cell reports · 2024Article
- Cancer driver mutations: predictions and reality.Trends in molecular medicine · 2023Review
- The frequency of somatic mutations in cancer predicts the phenotypic relevance of germline mutations.Frontiers in genetics · 2022Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Last, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR markedly improves genetic signals for hematologic malignancies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.