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000132796 1001_ $$00000-0001-5465-354X$$aColombo, Mara$$b0
000132796 245__ $$aThe BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.
000132796 260__ $$aNew York, NY [u.a.]$$bWiley-Liss$$c2018
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000132796 520__ $$aAlthough the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
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000132796 7001_ $$aMeeks, Huong D$$b2
000132796 7001_ $$aCaleca, Laura$$b3
000132796 7001_ $$aParsons, Michael T$$b4
000132796 7001_ $$aLi, Hongyan$$b5
000132796 7001_ $$aDe Vecchi, Giovanna$$b6
000132796 7001_ $$aTudini, Emma$$b7
000132796 7001_ $$aFoglia, Claudia$$b8
000132796 7001_ $$aMondini, Patrizia$$b9
000132796 7001_ $$aManoukian, Siranoush$$b10
000132796 7001_ $$aBehar, Raquel$$b11
000132796 7001_ $$aGarcia, Encarna B Gómez$$b12
000132796 7001_ $$aMeindl, Alfons$$b13
000132796 7001_ $$aMontagna, Marco$$b14
000132796 7001_ $$aNiederacher, Dieter$$b15
000132796 7001_ $$aSchmidt, Ane Y$$b16
000132796 7001_ $$aVaresco, Liliana$$b17
000132796 7001_ $$aWappenschmidt, Barbara$$b18
000132796 7001_ $$aBolla, Manjeet K$$b19
000132796 7001_ $$aDennis, Joe$$b20
000132796 7001_ $$aMichailidou, Kyriaki$$b21
000132796 7001_ $$aWang, Qin$$b22
000132796 7001_ $$aAittomäki, Kristiina$$b23
000132796 7001_ $$aAndrulis, Irene L$$b24
000132796 7001_ $$aAnton-Culver, Hoda$$b25
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000132796 7001_ $$aBeckmann, Matthias W$$b27
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000132796 7001_ $$aBenitez, Javier$$b29
000132796 7001_ $$aBoeckx, Bram$$b30
000132796 7001_ $$aBogdanova, Natalia V$$b31
000132796 7001_ $$aBojesen, Stig E$$b32
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000132796 7001_ $$aConroy, Don M$$b38
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000132796 7001_ $$aCross, Simon S$$b41
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000132796 7001_ $$aFasching, Peter A$$b46
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000132796 7001_ $$aGonzález-Neira, Anna$$b53
000132796 7001_ $$aGuénel, Pascal$$b54
000132796 7001_ $$aHaiman, Christopher A$$b55
000132796 7001_ $$aHall, Per$$b56
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000132796 7001_ $$aHartman, Mikael$$b58
000132796 7001_ $$aHauke, Jan$$b59
000132796 7001_ $$aHollestelle, Antoinette$$b60
000132796 7001_ $$aHopper, John L$$b61
000132796 7001_ $$aJakubowska, Anna$$b62
000132796 7001_ $$0P:(DE-He78)bce1fdec5ce564e2666156d96aeabec9$$aJung, Audrey$$b63$$udkfz
000132796 7001_ $$aKosma, Veli-Matti$$b64
000132796 7001_ $$aLambrechts, Diether$$b65
000132796 7001_ $$aLe Marchand, Loid$$b66
000132796 7001_ $$aLindblom, Annika$$b67
000132796 7001_ $$aLubinski, Jan$$b68
000132796 7001_ $$aMannermaa, Arto$$b69
000132796 7001_ $$aMargolin, Sara$$b70
000132796 7001_ $$aMiao, Hui$$b71
000132796 7001_ $$aMilne, Roger L$$b72
000132796 7001_ $$aNeuhausen, Susan L$$b73
000132796 7001_ $$aNevanlinna, Heli$$b74
000132796 7001_ $$aOlson, Janet E$$b75
000132796 7001_ $$aPeterlongo, Paolo$$b76
000132796 7001_ $$aPeto, Julian$$b77
000132796 7001_ $$aPylkäs, Katri$$b78
000132796 7001_ $$aSawyer, Elinor J$$b79
000132796 7001_ $$aSchmidt, Marjanka K$$b80
000132796 7001_ $$aSchmutzler, Rita K$$b81
000132796 7001_ $$aSchneeweiss, Andreas$$b82
000132796 7001_ $$aSchoemaker, Minouk J$$b83
000132796 7001_ $$aSee, Mee Hoong$$b84
000132796 7001_ $$aSouthey, Melissa C$$b85
000132796 7001_ $$aSwerdlow, Anthony$$b86
000132796 7001_ $$aTeo, Soo H$$b87
000132796 7001_ $$aToland, Amanda E$$b88
000132796 7001_ $$aTomlinson, Ian$$b89
000132796 7001_ $$aTruong, Thérèse$$b90
000132796 7001_ $$avan Asperen, Christi J$$b91
000132796 7001_ $$avan den Ouweland, Ans M W$$b92
000132796 7001_ $$avan der Kolk, Lizet E$$b93
000132796 7001_ $$aWinqvist, Robert$$b94
000132796 7001_ $$aYannoukakos, Drakoulis$$b95
000132796 7001_ $$aZheng, Wei$$b96
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000132796 7001_ $$aOffitt, Kenneth$$b103
000132796 7001_ $$aSide, Lucy E$$b104
000132796 7001_ $$avan Rensburg, Elizabeth J$$b105
000132796 7001_ $$aEmbrace, Study$$b106
000132796 7001_ $$aHebon, Study$$b107
000132796 7001_ $$aMcGuffog, Lesley$$b108
000132796 7001_ $$aAntoniou, Antonis C$$b109
000132796 7001_ $$aChenevix-Trench, Georgia$$b110
000132796 7001_ $$aSpurdle, Amanda B$$b111
000132796 7001_ $$aGoldgar, David E$$b112
000132796 7001_ $$aHoya, Miguel de la$$b113
000132796 7001_ $$aRadice, Paolo$$b114
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