biostudies-literatureBillaud AAIRC Foundation for Cancer ResearchUmberto Veronesi FoundationDutch Research Council (NWO)National Institute for Health Research (NIHR)104619https://www.ebi.ac.uk/biostudies/studies/S-EPMC12657754biostudies-literatureUnknown85The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays werBreast (Edinburgh, Scotland)Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer.PMC12657754NIHR203312IG22860NIHR203308184.021.007Mavroudis DShah MO'Brien KMKleibl ZDork TObi NSouthey MCNathanson KLNBCS CollaboratorsAhearn TULubinski JPalmer JRHoppe RAzzoni VEliassen HATeras LRCasamassima IDomchek SMMartinez MEWendt CSorensen CSHadjisavvas AHillemanns PHooning MJHu CSchmutzler RKCaleca LNeuhausen SLTruong TColombo MLush MBurnside ESDowty JGFigueroa JDPanayiotidis MINguyen-Dumont TZhao QBogdanova NVBonanni BYadav SBehrens SCamp NJKleiblova PPeterlongo PHaiman CGago-Dominguez MSpurdle ABPita GHodge JMWeitzel JNCampbell IGManoukian SSrivatsa JBodelon CDunning AMJames PARashid MUAndrulis ILKristensen VNHuang HAntoniou ACLesueur FGENESISGuenel PWeinberg CRWang QWinham SJEvans DGCouch FJAndrieu NBolla MKCessna MHDevereux LMilne RLChang-Claude JAuer PLChen FYao SMulligan AMHahnen EHowell AFasching PAGabrielson MJanatova MEriksson MSaloustros ERuddy KJMooser CTomlinson IFiglioli GHollestelle ARadice PBeckmann MWDevilee PGonzalez-Neira ACZECANCA consortiumCzene KPatel AVNewman WGSandler DPBoddicker NJDennis JSawyer EJHoya MOlson JERhenius VBillaud ALindstrom SBermisheva MCampbell ACastelao JEZirpoli GHamann UkConFab InvestigatorsJakubowska AStoppa-Lyonnet DSoukupova JBruning TfalseLarge-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer.The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays wer2025-01-01T00:00:00Z2025 Oct2026-06-05T21:14:26.675Z2026-05-21T03:13:10.726ZS-EPMC126577544122377010.1016/j.breast.2025.104619