ACMG标准和指南：序列变异的解释

StandardsandGuidelinesfortheInterpretationofSequenceVariants:AJointConsensusRecommendationoftheAmericanCollegeofMedicalGeneticsandGenomicsandtheAssociationforMolecularPathologySueRichards[Chair,ACMG],KnightDiagnosticLaboratories;DepartmentofMolecularandMedicalGenetics;OregonHealth&ScienceUniversity,Portland,OR,USANazneenAziz[CAP],CollegeofAmericanPathologists,Chicago,IL,USASherriBale[ACMG],GeneDx,Gaithersburg,MD,USADavidBick[ACMG],SectionofGenetics,DepartmentofPediatrics,MedicalCollegeofWisconsin,8701WatertownPlankRoad,Milwaukee,WI,USASomaDas[ACMG],DepartmentofHumanGenetics,ClinicalMolecularGeneticsLaboratory,TheUniversityofChicago,Chicago,USAJulieGastier-Foster[AMP],NationwideChildren'sHospital,Cytogenetics/MolecularGeneticsLaboratory;OhioStateUniversityCollegeofMedicine,DepartmentsofPathologyandPediatrics,Columbus,OH,USAUsersmayview,print,copy,anddownloadtextanddata-minethecontentinsuchdocuments,forthepurposesofacademicresearch,subjectalwaystothefullConditionsofuse::PhoenixChildren’sHospitalConflictsofInterest:Allworkgroupmembersareclinicalserviceproviders.NocommercialconflictofinterestwasreportedforSueRichards,DavidBick,SomaDas,WayneGrody,ElaineSpector,JulieGastier-Foster,NazneenAziz,andKarlVoelkerding.Thefollowingworkgroupmembershaveacommercialconflictofinterest:SherriBale(GeneDx,BioReference(stock),AdvisoryboardsforRainDance,Ingenuity);MadhuriHegde(Advisorfor:OxfordGeneticTechnologies,Tessarae,Ingenuity/Qiagen);ElaineLyon(AdvisoryboardforCompleteGenomics);andHeidiRehm(Scientificadvisoryboards:Ingenuity/Qiagen,CompleteGenomics,Knome,FocusedGenomics).Disclaimer:TheseACMGStandardsandGuidelinesweredevelopedprimarilyasaneducationalresourceforclinicallaboratorygeneticiststohelpthemprovidequalityclinicallaboratoryservices.Adherencetothesestandardsandguidelinesisvoluntaryanddoesnotnecessarilyassureasuccessfulmedicaloutcome.TheseStandardsandGuidelinesshouldnotbeconsideredinclusiveofallproperproceduresandtestsorexclusiveofotherproceduresandteststhatarereasonablydirectedtoobtainingthesameresults.Indeterminingtheproprietyofanyspecificprocedureortest,theclinicallaboratorygeneticistshouldapplyhisorherownprofessionaljudgmenttothespecificcircumstancespresentedbytheindividualpatientorspecimen.Clinicallaboratorygeneticistsareencouragedtodocumentinthepatient’srecordtherationalefortheuseofaparticularprocedureortest,whetherornotitisinconformancewiththeseStandardsandGuidelines.Theyalsoareadvisedtotakenoticeofthedateanyparticularguidelinewasadopted,andtoconsiderotherrelevantmedicalandscientificinformationthatbecomesavailableafterthatdate.Italsowouldbeprudenttoconsiderwhetherintellectualpropertyinterestsmayrestricttheperformanceofcertaintestsandotherprocedures.TheseStandardsandGuidelineswereapprovedbytheACMGBoardofDirectorsonDecember15,2014andtheAMPBoardofDirectorsonJanuary9,2015.HHSPublicAccessAuthormanuscriptGenetMed.Authormanuscript;availableinPMC2015November01.Publishedinfinaleditedformas:GenetMed.2015May;17(5):405–424.doi:10.1038/gim.2015.30.AuthorManuscriptAuthorManuscriptAuthorManuscriptAuthorManuscriptWayneW.Grody[ACMG],DepartmentsofPathology&LaboratoryMedicine,Pediatrics,andHumanGenetics,UCLASchoolofMedicine,LosAngeles,CA,USAMadhuriHegde[ACMG],EmoryGeneticsLaboratory,DepartmentofHumanGenetics,EmoryUniversity,Atlanta,Georgia,USAElaineLyon[AMP],DepartmentofPathology,ARUPInstituteforClinicalandExperimentalPathology,UniversityofUtah,SaltLakeCity,Utah,USAElaineSpector[ACMG],MolecularGeneticsLaboratory,Children’sHospitalColorado,DepartmentofPediatrics,UniversityofColoradoAnschutzMedicalSchool,Denver,CO,USAKarlVoelkerding[CAP],andDepartmentofPathology,ARUPInstituteforClinicalandExperimentalPathology,UniversityofUtah,SaltLakeCity,Utah,USAHeidiL.Rehm[Co-Chair,ACMG]onbehalfofOnbehalfoftheACMGLaboratoryQualityAssuranceCommitteePartnersLaboratoryforMolecularMedicineandDepartmentofPathology,Brigham&Women’sHospitalandHarvardMedicalSchool,Boston,Massachusetts,USAAbstractTheAmericanCollegeofMedicalGeneticsandGenomics(ACMG)previouslydevelopedguidancefortheinterpretationofsequencevariants.1Inthepastdecade,sequencingtechnologyhasevolvedrapidlywiththeadventofhigh-throughputnextgenerationsequencing.Byadoptingandleveragingnextgenerationsequencing,clinicallaboratoriesarenowperforminganeverincreasingcatalogueofgenetictestingspanninggenotyping,singlegenes,genepanels,exomes,genomes,transcriptomesandepigeneticassaysforgeneticdisorders.Byvirtueofincreasedcomplexity,thisparadigmshiftingenetictestinghasbeenaccompaniedbynewchallengesinsequenceinterpretation.Inthiscontext,theACMGconvenedaworkgroupin2013comprisedofrepresentativesfromtheACMG,theAssociationforMolecularPathology(AMP)andtheCollegeofAmericanPathologists(CAP)torevisitandrevisethestandardsandguidelinesfortheinterpretationofsequencevariants.Thegroupconsistedofclinicallaboratorydirectorsandclinicians.ThisreportrepresentsexpertopinionoftheworkgroupwithinputfromACMG,AMPandCAPstakeholders.Theserecommend