The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Colombo M, Lòpez-Perolio I, Meeks HD, Caleca L, Parsons MT, Li H, De Vecchi G, Tudini E, Foglia C, Mondini P, Manoukian S, Behar R, Garcia EBG, Meindl A, Montagna M, Niederacher D, Schmidt AY, Varesco L, Wappenschmidt B, Bolla MK, Dennis J, Michailidou K, Wang Q, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Beeghly-Fadel A, Benitez J, Boeckx B, Bogdanova NV, Bojesen SE, Bonanni B, Brauch H, Brenner H, Burwinkel B, Chang-Claude J, Conroy DM, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dörk T, Eriksson M, Fasching PA, Figueroa J, Fletcher O, Flyger H, Gabrielson M, García-Closas M, Giles GG, González-Neira A, Guénel P, Haiman CA, Hall P, Hamann U, Hartman M, Hauke J, Hollestelle A, Hopper JL, Jakubowska A, Jung A, Kosma VM, Lambrechts D, Le Marchand L, Lindblom A, Lubinski J, Mannermaa A, Margolin S, Miao H, Milne RL, Neuhausen SL, Nevanlinna H, Olson JE, Peterlongo P, Peto J, Pylkäs K, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, See MH, Southey MC, Swerdlow A, Teo SH, Toland AE, Tomlinson I, Truong T, van Asperen CJ, van den Ouweland AMW, van der Kolk LE, Winqvist R, Yannoukakos D, Zheng W, kConFab/AOCS Investigators, Dunning AM, Easton DF, Henderson A, Hogervorst FBL, Izatt L, Offitt K, Side LE, van Rensburg EJ, Embrace S, Hebon S, McGuffog L, Antoniou AC, Chenevix-Trench G, Spurdle AB, Goldgar DE, Hoya M, Radice P
Hum Mutat 39 729-741 01/01/2018


Although 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

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