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000179971 1001_ $$aDorling, Leila$$b0
000179971 245__ $$aBreast cancer risks associated with missense variants in breast cancer susceptibility genes.
000179971 260__ $$aLondon$$bBioMed Central$$c2022
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000179971 520__ $$aProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
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000179971 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000179971 650_7 $$2Other$$aBreast cancer
000179971 650_7 $$2Other$$aGenetic epidemiology
000179971 650_7 $$2Other$$aMissense variants
000179971 650_7 $$2Other$$aRisk prediction
000179971 7001_ $$aCarvalho, Sara$$b1
000179971 7001_ $$aAllen, Jamie$$b2
000179971 7001_ $$aParsons, Michael T$$b3
000179971 7001_ $$aFortuno, Cristina$$b4
000179971 7001_ $$aGonzález-Neira, Anna$$b5
000179971 7001_ $$aHeijl, Stephan M$$b6
000179971 7001_ $$aAdank, Muriel A$$b7
000179971 7001_ $$aAhearn, Thomas U$$b8
000179971 7001_ $$aAndrulis, Irene L$$b9
000179971 7001_ $$aAuvinen, Päivi$$b10
000179971 7001_ $$aBecher, Heiko$$b11
000179971 7001_ $$aBeckmann, Matthias W$$b12
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000179971 7001_ $$aBermisheva, Marina$$b14
000179971 7001_ $$aBogdanova, Natalia V$$b15
000179971 7001_ $$aBojesen, Stig E$$b16
000179971 7001_ $$aBolla, Manjeet K$$b17
000179971 7001_ $$aBremer, Michael$$b18
000179971 7001_ $$aBriceno, Ignacio$$b19
000179971 7001_ $$aCamp, Nicola J$$b20
000179971 7001_ $$aCampbell, Archie$$b21
000179971 7001_ $$aCastelao, Jose E$$b22
000179971 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b23$$udkfz
000179971 7001_ $$aChanock, Stephen J$$b24
000179971 7001_ $$aChenevix-Trench, Georgia$$b25
000179971 7001_ $$aNBCS Collaborators$$b26$$eCollaboration Author
000179971 7001_ $$aCollée, J Margriet$$b27
000179971 7001_ $$aCzene, Kamila$$b28
000179971 7001_ $$aDennis, Joe$$b29
000179971 7001_ $$aDörk, Thilo$$b30
000179971 7001_ $$aEriksson, Mikael$$b31
000179971 7001_ $$aEvans, D Gareth$$b32
000179971 7001_ $$aFasching, Peter A$$b33
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000179971 7001_ $$aJakubowska, Anna$$b55
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000179971 7001_ $$aLi, Jingmei$$b62
000179971 7001_ $$aLindblom, Annika$$b63
000179971 7001_ $$aLoizidou, Maria A$$b64
000179971 7001_ $$aLophatananon, Artitaya$$b65
000179971 7001_ $$aLubiński, Jan$$b66
000179971 7001_ $$aLuccarini, Craig$$b67
000179971 7001_ $$aMadsen, Michael J$$b68
000179971 7001_ $$aMannermaa, Arto$$b69
000179971 7001_ $$0P:(DE-He78)16b8745cffb0db0d366978d3afe17ebc$$aManoochehri, Mehdi$$b70
000179971 7001_ $$aMargolin, Sara$$b71
000179971 7001_ $$aMavroudis, Dimitrios$$b72
000179971 7001_ $$aMilne, Roger L$$b73
000179971 7001_ $$aMohd Taib, Nur Aishah$$b74
000179971 7001_ $$aMuir, Kenneth$$b75
000179971 7001_ $$aNevanlinna, Heli$$b76
000179971 7001_ $$aNewman, William G$$b77
000179971 7001_ $$aOosterwijk, Jan C$$b78
000179971 7001_ $$aPark, Sue K$$b79
000179971 7001_ $$aPeterlongo, Paolo$$b80
000179971 7001_ $$aRadice, Paolo$$b81
000179971 7001_ $$aSaloustros, Emmanouil$$b82
000179971 7001_ $$aSawyer, Elinor J$$b83
000179971 7001_ $$aSchmutzler, Rita K$$b84
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000179971 7001_ $$aTruong, Thérèse$$b92
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