{"doi":"10.1101/2025.07.14.664734","title":"Comprehensively Testing the Function of Missense Variation in the <i>STK11</i> Tumour Suppressor","abstract":"Abstract The tumor suppressor gene STK11 encoding Serine/Threonine Kinase 11 (STK11) is associated with Peutz-Jeghers Syndrome (PJS), a heritable gastrointestinal disease that increases lifetime cancer risk, and with somatic variation that contributes to ∼30% of lung and 20% of cervical cancers. Although identifying pathogenic variants is clinically actionable, over 94% of STK11 missense variants that have been observed clinically lack a definitive classification. We therefore measured the impact of STK11 variants at scale in a mammalian cell-based assay, scoring 6,026 (73% of all possible) amino acid substitutions across the full-length gene. Functional scores—which were consistent with biochemical properties, smaller-scale assays, and pathogenicity annotations—identified a subset of PJS patients with germline STK11 variants diagnosed later in life, as well as somatic STK11 variants found in cancer patients that had comparable overall survival estimates to wild-type STK11 . Our scores provided new evidence for 350 annotated VUS STK11 missense variants and ∼80% of missense variants that have not yet been reported clinically, but we might expect to observe in the future. Thus, our effect map provides a proactive resource for gaining sequence-structure-function insights and evidence for actionable interpretation of clinical missense variants.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571579,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":106211,"name":"Atina G. Coté","orcid":"0000-0002-0340-9325","position":1,"is_corresponding":false},{"id":1041591,"name":"Warren van Loggerenberg","orcid":"0000-0002-4912-1044","position":2,"is_corresponding":false},{"id":106215,"name":"Marinella Gebbia","orcid":"0000-0002-2550-2141","position":3,"is_corresponding":false},{"id":106217,"name":"Nishka Kishore","orcid":"0000-0002-9219-4310","position":4,"is_corresponding":false},{"id":297962,"name":"Jochen Weile","orcid":"0000-0003-1628-9390","position":5,"is_corresponding":false},{"id":106249,"name":"Roujia Li","orcid":null,"position":6,"is_corresponding":false},{"id":1162626,"name":"Chloe Reno","orcid":"0009-0009-9332-0831","position":7,"is_corresponding":false},{"id":583334,"name":"Ashley P.L. Marsh","orcid":"0000-0001-6049-6931","position":8,"is_corresponding":false},{"id":631748,"name":"Felicia Hernandez","orcid":null,"position":9,"is_corresponding":false},{"id":58555,"name":"Preksha Shahagadkar","orcid":"0009-0005-7842-8095","position":10,"is_corresponding":false},{"id":424760,"name":"Lauren Grove","orcid":"0000-0002-0583-0092","position":11,"is_corresponding":false},{"id":13802,"name":"Samuel R. Meier","orcid":"0000-0002-7026-2722","position":12,"is_corresponding":false},{"id":58562,"name":"Hsin-Jung Wu","orcid":"0009-0005-3474-6171","position":13,"is_corresponding":false},{"id":131763,"name":"Silvia Fenoglio","orcid":null,"position":14,"is_corresponding":false},{"id":58528,"name":"Leanne G. Ahronian","orcid":"0000-0001-7233-5879","position":15,"is_corresponding":false},{"id":1477690,"name":"Teng Teng","orcid":"0009-0001-6018-656X","position":16,"is_corresponding":false},{"id":1027864,"name":"Andrew Waters","orcid":"0000-0001-5905-399X","position":17,"is_corresponding":false},{"id":746325,"name":"David J. Seward","orcid":"0000-0001-5821-6187","position":18,"is_corresponding":false},{"id":706262,"name":"Mikko Taipale","orcid":"0000-0003-3811-1761","position":19,"is_corresponding":false},{"id":393465,"name":"Melyssa Aronson","orcid":"0000-0002-7503-5799","position":20,"is_corresponding":false},{"id":74278,"name":"Marcy E. Richardson","orcid":"0000-0002-4626-4920","position":21,"is_corresponding":false},{"id":13189,"name":"David J. Adams","orcid":"0000-0001-9490-0306","position":22,"is_corresponding":false},{"id":106276,"name":"Frederick P. Roth","orcid":"0000-0002-6628-649X","position":23,"is_corresponding":false},{"id":1237552,"name":"Daniel Zimmerman","orcid":"0009-0003-2264-6769","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:57:19.669553Z","pmid":"40791513","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}