Georgeson PHarrison TAPope BJZaidi SHQu CSteinfelder RSLin YJoo JEMahmood KClendenning MWalker RAmitay ELBerndt SIBrenner HCampbell PTCao YChan ATChang-Claude JDoheny KFDrew DAFigueiredo JCFrench AJGallinger SGiannakis MGiles GGGsur AGunter MJHoffmeister MHsu LHuang W-YLimburg PManson JEMoreno VNassir RNowak JAObón-Santacana MOgino SPhipps AIPotter JDSchoen RESun WToland AETrinh QMUgai TMacrae FARosty CHudson TJJenkins MAThibodeau SNWinship IMPeters UBuchanan DD2023-07-052022-05-242023-07-056/06/2022Nat Commun, 2022, 13 (1), pp. 3254 - ?https://hdl.handle.net/10179/18382(c) The Author/sCarriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.3254 - ?Colorectal NeoplasmsDNA GlycosylasesDNA Mutational AnalysisGenetic Predisposition to DiseaseGerm-Line MutationHeterozygoteHumansMutationJournal article10.1038/s41467-022-30916-14539732041-1723Massey_Dark