ACMG标准和指南序列变异的解释

1©AmericanCollegeofMedicalGeneticsandGenomicsACMGStAndArdSAndGuidelineSSubmitted28January2015;accepted28January2015;advanceonlinepublication5March2015.doi:10.1038/gim.2015.30GenetMed00002015GeneticsinMedicine10.1038/gim.2015.30ACMGStandardsandGuidelines000028January201528January2015©AmericanCollegeofMedicalGeneticsandGenomics5March2015TheAmericanCollegeofMedicalGeneticsandGenomics(ACMG)previouslydevelopedguidancefortheinterpretationofsequencevariants.1Inthepastdecade,sequencingtechnologyhasevolvedrapidlywiththeadventofhigh-throughputnext-generationsequencing.Byadoptingandleveragingnext-generationsequencing,clinicallaboratoriesarenowperforminganever-increasingcatalogueofgenetictestingspanninggenotyping,singlegenes,genepanels,exomes,genomes,transcriptomes,andepigeneticassaysforgeneticdisorders.Byvirtueofincreasedcomplexity,thisshiftingenetictestinghasbeenaccompaniedbynewchallengesinsequenceinterpretation.InthiscontexttheACMGconvenedaworkgroupin2013comprisingrepre-sentativesfromtheACMG,theAssociationforMolecularPathology(AMP),andtheCollegeofAmericanPathologiststorevisitandrevisethestandardsandguidelinesfortheinterpretationofsequencevariants.Thegroupconsistedofclinicallaboratorydirectorsandclinicians.ThisreportrepresentsexpertopinionoftheworkgroupwithinputfromACMG,AMP,andCollegeofAmericanPathologistsstakeholders.Theserecommendationsprimarilyapplytothebreadthofgenetictestsusedinclinicallaboratories,includinggenotyping,singlegenes,panels,exomes,andgenomes.Thisreportrecommendstheuseofspecificstan-dardterminology—“pathogenic,”“likelypathogenic,”“uncertainsig-nificance,”“likelybenign,”and“benign”—todescribevariantsidentifiedingenesthatcauseMendeliandisorders.Moreover,thisrecommenda-tiondescribesaprocessforclassifyingvariantsintothesefivecategoriesbasedoncriteriausingtypicaltypesofvariantevidence(e.g.,populationdata,computationaldata,functionaldata,segregationdata).Becauseoftheincreasedcomplexityofanalysisandinterpretationofclinicalgenetictestingdescribedinthisreport,theACMGstronglyrecom-mendsthatclinicalmoleculargenetictestingshouldbeperformedinaClinicalLaboratoryImprovementAmendments–approvedlaboratory,withresultsinterpretedbyaboard-certifiedclinicalmoleculargeneticistormoleculargeneticpathologistortheequivalent.GenetMedadvanceonlinepublication5March2015KeyWords:ACMGlaboratoryguideline;clinicalgenetictesting;interpretation;reporting;sequencevariantterminology;variantreporting1DepartmentofMolecularandMedicalGenetics,KnightDiagnosticLaboratories,OregonHealth&ScienceUniversity,Portland,Oregon,USA;2CollegeofAmericanPathologists,Chicago,Illinois,USA;3GeneDx,Gaithersburg,Maryland,USA;4DepartmentofPediatrics,SectionofGenetics,MedicalCollegeofWisconsin,Milwaukee,Wisconsin,USA;5DepartmentofHumanGenetics,ClinicalMolecularGeneticsLaboratory,TheUniversityofChicago,Chicago,Illinois,USA;6Cytogenetics/MolecularGeneticsLaboratory,NationwideChildren’sHospital,Columbus,Ohio,USA;7DepartmentofPathology,OhioStateUniversityCollegeofMedicine,Columbus,Ohio,USA;8DepartmentofPediatrics,OhioStateUniversityCollegeofMedicine,Columbus,Ohio,USA;9DepartmentofPathologyandLaboratoryMedicine,UniversityofCaliforniaLosAngelesSchoolofMedicine,LosAngeles,California,USA;10DepartmentofPediatrics,UniversityofCaliforniaLosAngelesSchoolofMedicine,LosAngeles,California,USA;11DepartmentofHumanGenetics,UniversityofCaliforniaLosAngelesSchoolofMedicine,LosAngeles,California,USA;12DepartmentofHumanGenetics,EmoryGeneticsLaboratory,EmoryUniversity,Atlanta,Georgia,USA;13DepartmentofPathology,ARUPInstituteforClinicalandExperimentalPathology,UniversityofUtah,SaltLakeCity,Utah,USA;14DepartmentofPediatrics,MolecularGeneticsLaboratory,Children’sHospitalColorado,UniversityofColoradoAnschutzMedicalSchool,Denver,Colorado,USA;15PartnersLaboratoryforMolecularMedicineandDepartmentofPathology,Brigham&Women’sHospitalandHarvardMedicalSchool,Boston,Massachusetts,USA;16Currentaffiliation:PhoenixChildren’sHospital,Phoenix,Arizona,USA.Correspondence:SueRichards([e-mail])ApprovedbytheACMGBoardofDirectorson15December2014andtheAMPBoardofDirectorson9January2015.Standardsandguidelinesfortheinterpretationofsequencevariants:ajointconsensusrecommendationoftheAmericanCollegeofMedicalGeneticsandGenomicsandtheAssociationforMolecularPathologySue Richards,PhD1,Nazneen Aziz,PhD2,16,Sherri Bale,PhD3,David Bick,MD4,Soma Das,PhD5,Julie Gastier-Foster,PhD6,7,8,Wayne W. Grody,MD,PhD9,10,11,Madhuri Hegde,PhD12,Elaine Lyon,PhD13,Elaine Spector,PhD14,Karl Voelkerding,MD13andHeidi L. Rehm,PhD15;onbehalfoftheACMGLaboratoryQualityAssuranceCommitteeDisclaimer:TheseACMGStandardsandGuidelinesweredevelopedprimarilyasaneducationalresourceforclinicallaboratorygeneticiststohelpthempro-videqualityclinicallaboratoryservices.Adherencetothesestandardsandguidelinesisvoluntaryanddoesnotnecessarilyassureasuccessfulmedicaloutcome.TheseStandardsandGuidelinesshouldnotbeconsideredinclusiveofallproperproceduresandtestsorexclusiveofotherproceduresandteststhatarereason-ablydirectedtoobtainingthesameresults.Indeterminingt