ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.
Lenka StolarovaPetra KleiblovaPetra ZemankovaBarbora StastnaMarketa JanatovaJana SoukupovaMaria Isabel Waddington AchatzChristine B AmbrosoneParaskevi ApostolouBanu K ArunPaul L AuerMollie E BarnardBirgitte Bertelsennull nullMarinus J BlokNicholas J BoddickerJoan BrunetElizabeth S BurnsideMariarosaria CalvelloIan G CampbellSock Hoai ChanFei ChenJian Bang ChiangAnna CoppaLaura CortesiAna Crujeiras-Gonzáleznull nullKim De LeeneerRobin de PutterAllison DePersiaLisa DevereuxSusan M DomchekAnna EfremidisChristoph EngelCorinna ErnstDafydd Gareth EvansLidia FeliubadalóFlorentia FostiraOlivia Fuentes-RíosEncarna B Gómez-GarcíaSara GonzálezChristopher A HaimanThomas Van Overeem HansenJan HaukeJames M HodgeChunling HuHongyan HuangNur Diana Binte IshakYusuke IwasakiIrene KonstantopoulouPeter KraftJames V LaceyConxi Lazaro GarciaNa LiWeng Khong LimSara LindströmAdriana LoriMaría Elena MartínezAlexandra MartinsKoichi MatsudaGiuseppe MatulloSimone McInernyKyriaki MichailidouMarco MontagnaAlvaro N A MonteiroLuigi MoriKatherine L NathansonSusan L NeuhausenHeli NevanlinnaJanet E OlsonJulie R PalmerBarbara PasiniAlpa V PatelMaria PianeBruce PoppePaolo RadiceAlessandra RenieriNicoletta RestaMarcy E RichardsonToon RosseelKathryn J RuddyMarta SantamariñaElizabeth Santana Dos SantosLauren R TerasAmanda Ewart TolandAmy Trentham-DietzCeline M VachonAlexander E VolkNana Weber-LassalleJeffrey N WeitzelLisa WiesmullerStacey J WinhamSiddhartha YadavDrakoulis YannoukakosSong YaoValentina ZampigaMagnus ZethovenZe Wen ZhangTomáš ZimaAmanda B SpurdleAna VegaMaria RossingJesús Del ValleArcangela De NicoloEric HahnenKathleen B M ClaesJoanne Ngeow Yuen YieYukihide MomozawaPaul A JamesFergus J CouchLibor MacůrekZdenek KleiblPublished in: Clinical cancer research : an official journal of the American Association for Cancer Research (2023)
We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.