Two truncating variants in FANCC and breast cancer risk
Authors: Dörk Thilo , Peterlongo Paolo , Mannermaa Arto , Bolla Manjeet K. , Wang Qin , Dennis Joe , Ahearn Thomas , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Aronson Kristan J. , Augustinsson Annelie , Freeman Laura E. Beane , Beckmann Matthias W. , Beeghly-Fadiel Alicia , Behrens Sabine , Bermisheva Marina , Blomqvist Carl , Bogdanova Natalia V. , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Burwinkel Barbara , Canzian Federico , Chan Tsun L. , Chang-Claude Jenny , Chanock Stephen J. , Choi Ji-Yeob , Christiansen Hans , Clarke Christine L. , Couch Fergus J. , Czene Kamila , Daly Mary B. , dos-Santos-Silva Isabel , Dwek Miriam , Eccles Diana M. , Ekici Arif B. , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine , Flyger Henrik , Fritschi Lin , Gabrielson Marike , Gago-Dominguez Manuela , Gao Chi , Gapstur Susan M. , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Giles Graham G. , Goldberg Mark S. , Goldgar David E. , Guénel Pascal , Haeberle Lothar , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Hartman Mikael , Hauke Jan , Hein Alexander , Hillemanns Peter , Hogervorst Frans B. L. , Hooning Maartje J. , Hopper John L. , Howell Tony , Huo Dezheng , Ito Hidemi , Iwasaki Motoki , Jakubowska Anna , Janni Wolfgang , John Esther M. , Jung Audrey , Kaaks Rudolf , Kang Daehee , Kapoor Pooja Middha , Khusnutdinova Elza , Kim Sung-Won , Kitahara Cari M. , Koutros Stella , Kraft Peter , Kristensen Vessela N. , Kwong Ava , Lambrechts Diether , Marchand Loic Le , Li Jingmei , Lindström Sara , Linet Martha , Lo Wing-Yee , Long Jirong , Lophatananon Artitaya , Lubiński Jan , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martinez Elena , Matsuo Keitaro , Mavroudis Dimitris , Meindl Alfons , Menon Usha , Milne Roger L. , Mohd Taib Nur Aishah , Muir Kenneth , Mulligan Anna Marie , Neuhausen Susan L. , Nevanlinna Heli , Neven Patrick , Newman William G. , Offit Kenneth , Olopade Olufunmilayo I. , Olshan Andrew F. , Olson Janet E. , Olsson Håkan , Park Sue K. , Park-Simon Tjoung-Won , Peto Julian , Plaseska-Karanfilska Dijana , Pohl-Rescigno Esther , Presneau Nadege , Rack Brigitte , Radice Paolo , Rashid Muhammad U. , Rennert Gad , Rennert Hedy S. , Romero Atocha , Ruebner Matthias , Saloustros Emmanouil , Schmidt Marjanka K. , Schmutzler Rita K. , Schneider Michael O. , Schoemaker Minouk J. , Scott Christopher , Shen Chen-Yang , Shu Xiao-Ou , Simard Jacques , Slager Susan , Smichkoska Snezhana , Southey Melissa C. , Spinelli John J. , Stone Jennifer , Surowy Harald , Swerdlow Anthony J. , Tamimi Rulla M. , Tapper William J. , Teo Soo H. , Terry Mary Beth , Toland Amanda E. , Tollenaar Rob A. E. M. , Torres Diana , Torres-Mejía Gabriela , Troester Melissa A. , Truong Thérèse , Tsugane Shoichiro , Untch Michael , Vachon Celine M. , Ouweland Ans M. W. van den , Veen Elke M. van , Vijai Joseph , Wendt Camilla , Wolk Alicja , Yu Jyh-Cherng , Zheng Wei , Ziogas Argyrios , Ziv Elad ,   ABCTB Investigators, Balleine Rosemary , Baxter Robert , Braye Stephen , Carpenter Jane , Dahlstrom Jane , Forbes John , Lee C. Soon , Marsh Deborah , Morey Adrienne , Pathmanathan Nirmala , Scott Rodney , Simpson Peter , Spigelman Allan , Wilcken Nicholas , Yip Desmond , Zeps Nikolajs ,   NBCS Collaborators, Børresen-Dale Anne-Lise , Grenaker Alnæs Grethe I. , Sahlberg Kristine K. , Ottestad Lars , Kåresen Rolf , Schlichting Ellen , Holmen Marit Muri , Sauer Toril , Haakensen Vilde , Engebråten Olav , Naume Bjørn , Fosså Alexander , Kiserud Cecile E. , Reinertsen Kristin V. , Helland Åslaug , Riis Margit , Geisler Jürgen , Dunning Alison M. , Pharoah Paul D. P. , Schindler Detlev , Devilee Peter , Easton Douglas F. 
Published: August 2019

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.