FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
Authors: Figlioli Gisella , Billaud Amandine , Ahearn Thomas U. , Antonenkova Natalia N. , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Blok Marinus J. , Bogdanova Natalia V. , Bonanni Bernardo , Burwinkel Barbara , Camp Nicola J. , Campbell Archie , Castelao Jose E. , Cessna Melissa H. , Chanock Stephen J. ,   NBCS Collaborators, Sahlberg Kristine K. , Børresen-Dale Anne-Lise , Gram Inger Torhild , Olsen Karina Standahl , Engebråten Olav , Naume Bjørn , Geisler Jürgen ,   OSBREAC, Bathen Tone F. , Borgen Elin , Fritzman Britt , Garred Øystein , Geitvik Gry Aarum , Hofvind Solveig , Langerød Anita , Lingjærde Ole Christian , Mælandsmo Gunhild Mari , Russnes Hege G. , Skjerven Helle Kristine , Sørlie Therese , Alnæs Grethe I. Grenaker , Czene Kamila , Devilee Peter , Dörk Thilo , Engel Christoph , Eriksson Mikael , Fasching Peter A. , Figueroa Jonine D. , Gabrielson Marike , Gago-Dominguez Manuela , García-Closas Montserrat , González-Neira Anna , Grassmann Felix , Guénel Pascal , Gündert Melanie , Hadjisavvas Andreas , Hahnen Eric , Hall Per , Hamann Ute , Harrington Patricia A. , He Wei , Hillemanns Peter , Hollestelle Antoinette , Hooning Maartje J. , Hoppe Reiner , Howell Anthony , Humphreys Keith ,   KConFab Investigators, Amor David , Andrews Lesley , Antill Yoland , Balleine Rosemary , Beesley Jonathan , Bennett Ian , Bogwitz Michael , Botes Leon , Brennan Meagan , Brown Melissa , Buckley Michael , Burke Jo , Butow Phyllis , Caldon Liz , Campbell Ian , Cao Michelle , Chakrabarti Anannya , Chauhan Deepa , Chauhan Manisha , Christian Alice , Cohen Paul , Colley Alison , Crook Ashley , Cui James , Courtney Eliza , Cummings Margaret , Dawson Sarah-Jane , deFazio Anna , Delatycki Martin , Dickson Rebecca , Dixon Joanne , Edkins Ted , Edwards Stacey , Farshid Gelareh , Fellows Andrew , Fenton Georgina , Field Michael , Flanagan James , Fong Peter , Forrest Laura , Fox Stephen , French Juliet , Friedlander Michael , Gaff Clara , Gattas Mike , George Peter , Greening Sian , Harris Marion , Hart Stewart , Hayward Nick , Hopper John , Hoskins Cass , Hunt Clare , James Paul , Jenkins Mark , Kidd Alexa , Kirk Judy , Koehler Jessica , Kollias James , Lakhani Sunil , Lawrence Mitchell , Lee Jason , Li Shuai , Lindeman Geoff , Lipton Lara , Lobb Liz , Loi Sherene , Mann Graham , Marsh Deborah , McLachlan Sue Anne , Meiser Bettina , Milne Roger , Nightingale Sophie , O’Connell Shona , O’Sullivan Sarah , Ortega David Gallego , Pachter Nick , Pang Jia-Min , Pathak Gargi , Patterson Briony , Pearn Amy , Phillips Kelly , Pieper Ellen , Ramus Susan , Rickard Edwina , Robinson Bridget , Saleh Mona , Skandarajah Anita , Salisbury Elizabeth , Saunders Christobel , Saunus Jodi , Scott Rodney , Scott Clare , Sexton Adrienne , Shelling Andrew , Simpson Peter , Southey Melissa , Spurdle Amanda , Taylor Jessica , Taylor Renea , Thorne Heather , Trainer Alison , Tucker Kathy , Visvader Jane , Walker Logan , Williams Rachael , Winship Ingrid , Young Mary Ann , Zaheed Milita , Jager Agnes , Jakubowska Anna , Khusnutdinova Elza K. , Ko Yon-Dschun , Kristensen Vessela N. , Lindblom Annika , Lissowska Jolanta , Lubiński Jan , Mannermaa Arto , Manoukian Siranoush , Margolin Sara , Mavroudis Dimitrios , Newman William G. , Obi Nadia , Panayiotidis Mihalis I. , Rashid Muhammad U. , Rhenius Valerie , Rookus Matti A. , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Shah Mitul , Sironen Reijo , Southey Melissa C. , Suvanto Maija , Tollenaar Rob A. E. M. , Tomlinson Ian , Truong Thérèse , van der Kolk Lizet E. , van Veen Elke M. , Wappenschmidt Barbara , Yang Xiaohong R. , Bolla Manjeet K. , Dennis Joe , Dunning Alison M. , Easton Douglas F. , Lush Michael , Michailidou Kyriaki , Pharoah Paul D. P. , Wang Qin , Adank Muriel A. , Schmidt Marjanka K. , Andrulis Irene L. , Chang-Claude Jenny , Nevanlinna Heli , Chenevix-Trench Georgia , Evans D. Gareth , Milne Roger L. , Radice Paolo , Peterlongo Paolo 
Published: January 2023

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) inFANCMconfer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association betweenFANCMmissense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689FANCMMVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04;P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated thatFANCMMVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38;P = 0.002). Our results support the definition from previous analyses ofFANCMas a moderate-risk breast cancer gene and provide evidence thatFANCMMVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due toFANCMMVs.