Breast cancer risks associated with missense variants in breast cancer susceptibility genes

NBCS Collaborators; kConFab Investigators; L Dorling; S Carvalho; J Allen; MT Parsons; C Fortuno; A González-Neira; SM Heijl; MA Adank; TU Ahearn; IL Andrulis; P Auvinen; H Becher; Matthias W Beckmann; Sabine Behrens; Marina Bermisheva; Natalia V. Bogdanova; Stig E Bojesen; Manjeet K. Bolla; Michael Bremer; Ignacio Briceno; Nicola J. Camp; Archie Campbell; Jose E Castelao; Jenny Chang-Claude; Stephen J Chanock; Georgia Chenevix-Trench; J Margriet Collée; Kamila Czene; Joe Dennis; Thilo Dörk; Mikael Eriksson; D Gareth Evans; Peter A Fasching; Jonine Figueroa; Henrik Flyger; Marike Gabrielson; Manuela Gago Dominguez; Montserrat García-Closas; Graham G. Giles; Gord Glendon; Pascal Guénel; Melanie Gündert; Andreas Hadjisavvas; Eric Hahnen; Per Hall; Ute Hamann; Elaine Harkness; Mikael Hartman; Frans B. L. Hogervorst; Antoinette Hollestelle; Reiner Hoppe; Tony Howell; Anna Jakubowska; Audrey Jung; Elza Khusnutdinova; Sung-Won Kim; Yon Dschun Ko; Vessela N. Kristensen; Inge M. M. Lakeman; Jingmei Li; Annika Lindblom; Maria A Loizidou; Artitaya Lophatananon; Jan Lubiński; Craig Luccarini; Michael J. Madsen; Arto Mannermaa; Mehdi Manoochehri; Sara Margolin; Dimitrios Mavroudis; Roger L. Milne; Nur Aishah Mohd Taib; Kenneth Muir; Heli Nevanlinna; William Newman; Jan C Oosterwijk; Sue K Park; Paolo Peterlongo; Paolo Radice; Emmanouil Saloustros; Elinor J. Sawyer; Rita K Schmutzler; Mitul Shah; Xueling Sim; Melissa C Southey; Harald Surowy; Maija Suvanto; Ian Tomlinson; Diana Torres; Thérèse Truong; Christi J. Van Asperen; Regina Waltes; Qin Wang; Xiaohong R. Yang; Paul D.P. Pharoah; Marjanka K. Schmidt; Javier Benitez; Bas Vroling; Alison M. Dunning; Soo Hwang Teo; Anders Kvist; Miguel De la Hoya; Peter Devilee; Amanda B Spurdle; Maaike P G Vreeswijk; Douglas F Easton

doi:10.1101/2021.09.02.21262369

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

NBCS Collaborators, kConFab Investigators, L Dorling, S Carvalho, J Allen, MT Parsons, C Fortuno, A González-Neira, SM Heijl, MA Adank, TU Ahearn, IL Andrulis, P Auvinen, H Becher, Matthias W Beckmann, Sabine Behrens, Marina Bermisheva, Natalia V. Bogdanova, Stig E Bojesen, Manjeet K. BollaMichael Bremer, Ignacio Briceno, Nicola J. Camp, Archie Campbell, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Georgia Chenevix-Trench, J Margriet Collée, Kamila Czene, Joe Dennis, Thilo Dörk, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago Dominguez, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Elaine Harkness, Mikael Hartman, Frans B. L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, Tony Howell, Anna Jakubowska, Audrey Jung, Elza Khusnutdinova, Sung-Won Kim, Yon Dschun Ko, Vessela N. Kristensen, Inge M. M. Lakeman, Jingmei Li, Annika Lindblom, Maria A Loizidou, Artitaya Lophatananon, Jan Lubiński, Craig Luccarini, Michael J. Madsen, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Nur Aishah Mohd Taib, Kenneth Muir, Heli Nevanlinna, William Newman, Jan C Oosterwijk, Sue K Park, Paolo Peterlongo, Paolo Radice, Emmanouil Saloustros, Elinor J. Sawyer, Rita K Schmutzler, Mitul Shah, Xueling Sim, Melissa C Southey, Harald Surowy, Maija Suvanto, Ian Tomlinson, Diana Torres, Thérèse Truong, Christi J. Van Asperen, Regina Waltes, Qin Wang, Xiaohong R. Yang, Paul D.P. Pharoah, Marjanka K. Schmidt, Javier Benitez, Bas Vroling, Alison M. Dunning, Soo Hwang Teo, Anders Kvist, Miguel De la Hoya, Peter Devilee, Amanda B Spurdle, Maaike P G Vreeswijk, Douglas F Easton

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Protein 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.

Methods: Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), 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.

Results: 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.

Conclusions: 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.

Original language	English
Pages (from-to)	1-36
Number of pages	36
Journal	medRxiv
DOIs	https://doi.org/10.1101/2021.09.02.21262369
Publication status	Published - 15 Sept 2021

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10.1101/2021.09.02.21262369

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NBCS Collaborators, kConFab Investigators, Dorling, L., Carvalho, S., Allen, J., Parsons, MT., Fortuno, C., González-Neira, A., Heijl, SM., Adank, MA., Ahearn, TU., Andrulis, IL., Auvinen, P., Becher, H., Beckmann, M. W., Behrens, S., Bermisheva, M., Bogdanova, N. V., Bojesen, S. E., ... Easton, D. F. (2021). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. medRxiv, 1-36. https://doi.org/10.1101/2021.09.02.21262369

@article{6aa4da6dc5b946ea83c3dc78319665ed,

title = "Breast cancer risks associated with missense variants in breast cancer susceptibility genes",

abstract = "Background: Protein 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.Methods: Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), 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.Results: 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.Conclusions: 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.",

author = "{NBCS Collaborators} and {kConFab Investigators} and L Dorling and S Carvalho and J Allen and MT Parsons and C Fortuno and A Gonz{\'a}lez-Neira and SM Heijl and MA Adank and TU Ahearn and IL Andrulis and P Auvinen and H Becher and Beckmann, {Matthias W} and Sabine Behrens and Marina Bermisheva and Bogdanova, {Natalia V.} and Bojesen, {Stig E} and Bolla, {Manjeet K.} and Michael Bremer and Ignacio Briceno and Camp, {Nicola J.} and Archie Campbell and Castelao, {Jose E} and Jenny Chang-Claude and Chanock, {Stephen J} and Georgia Chenevix-Trench and Coll{\'e}e, {J Margriet} and Kamila Czene and Joe Dennis and Thilo D{\"o}rk and Mikael Eriksson and Evans, {D Gareth} and Fasching, {Peter A} and Jonine Figueroa and Henrik Flyger and Marike Gabrielson and Dominguez, {Manuela Gago} and Montserrat Garc{\'i}a-Closas and Giles, {Graham G.} and Gord Glendon and Pascal Gu{\'e}nel and Melanie G{\"u}ndert and Andreas Hadjisavvas and Eric Hahnen and Per Hall and Ute Hamann and Elaine Harkness and Mikael Hartman and Hogervorst, {Frans B. L.} and Antoinette Hollestelle and Reiner Hoppe and Tony Howell and Anna Jakubowska and Audrey Jung and Elza Khusnutdinova and Sung-Won Kim and Ko, {Yon Dschun} and Kristensen, {Vessela N.} and Lakeman, {Inge M. M.} and Jingmei Li and Annika Lindblom and Loizidou, {Maria A} and Artitaya Lophatananon and Jan Lubi{\'n}ski and Craig Luccarini and Madsen, {Michael J.} and Arto Mannermaa and Mehdi Manoochehri and Sara Margolin and Dimitrios Mavroudis and Milne, {Roger L.} and Taib, {Nur Aishah Mohd} and Kenneth Muir and Heli Nevanlinna and William Newman and Oosterwijk, {Jan C} and Park, {Sue K} and Paolo Peterlongo and Paolo Radice and Emmanouil Saloustros and Sawyer, {Elinor J.} and Schmutzler, {Rita K} and Mitul Shah and Xueling Sim and Southey, {Melissa C} and Harald Surowy and Maija Suvanto and Ian Tomlinson and Diana Torres and Th{\'e}r{\`e}se Truong and {Van Asperen}, {Christi J.} and Regina Waltes and Qin Wang and Yang, {Xiaohong R.} and Pharoah, {Paul D.P.} and Schmidt, {Marjanka K.} and Javier Benitez and Bas Vroling and Dunning, {Alison M.} and Teo, {Soo Hwang} and Anders Kvist and {De la Hoya}, Miguel and Peter Devilee and Spurdle, {Amanda B} and Vreeswijk, {Maaike P G} and Easton, {Douglas F}",

year = "2021",

month = sep,

day = "15",

doi = "10.1101/2021.09.02.21262369",

language = "English",

pages = "1--36",

journal = "medRxiv",

publisher = "Cold Spring Harbor Laboratory Press",

}

NBCS Collaborators, kConFab Investigators, Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, González-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collée, JM, Czene, K, Dennis, J, Dörk, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Dominguez, MG, García-Closas, M, Giles, GG, Glendon, G, Guénel, P, Gündert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, E, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, T, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, YD, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubiński, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Muir, K, Nevanlinna, H, Newman, W, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, Van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, De la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG & Easton, DF 2021, 'Breast cancer risks associated with missense variants in breast cancer susceptibility genes', medRxiv, pp. 1-36. https://doi.org/10.1101/2021.09.02.21262369

TY - JOUR

T1 - Breast cancer risks associated with missense variants in breast cancer susceptibility genes

AU - NBCS Collaborators

AU - kConFab Investigators

AU - Dorling, L

AU - Carvalho, S

AU - Allen, J

AU - Parsons, MT

AU - Fortuno, C

AU - González-Neira, A

AU - Heijl, SM

AU - Adank, MA

AU - Ahearn, TU

AU - Andrulis, IL

AU - Auvinen, P

AU - Becher, H

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E

AU - Bolla, Manjeet K.

AU - Bremer, Michael

AU - Briceno, Ignacio

AU - Camp, Nicola J.

AU - Campbell, Archie

AU - Castelao, Jose E

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Chenevix-Trench, Georgia

AU - Collée, J Margriet

AU - Czene, Kamila

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Eriksson, Mikael

AU - Evans, D Gareth

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Gabrielson, Marike

AU - Dominguez, Manuela Gago

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Guénel, Pascal

AU - Gündert, Melanie

AU - Hadjisavvas, Andreas

AU - Hahnen, Eric

AU - Hall, Per

AU - Hamann, Ute

AU - Harkness, Elaine

AU - Hartman, Mikael

AU - Hogervorst, Frans B. L.

AU - Hollestelle, Antoinette

AU - Hoppe, Reiner

AU - Howell, Tony

AU - Jakubowska, Anna

AU - Jung, Audrey

AU - Khusnutdinova, Elza

AU - Kim, Sung-Won

AU - Ko, Yon Dschun

AU - Kristensen, Vessela N.

AU - Lakeman, Inge M. M.

AU - Li, Jingmei

AU - Lindblom, Annika

AU - Loizidou, Maria A

AU - Lophatananon, Artitaya

AU - Lubiński, Jan

AU - Luccarini, Craig

AU - Madsen, Michael J.

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Margolin, Sara

AU - Mavroudis, Dimitrios

AU - Milne, Roger L.

AU - Taib, Nur Aishah Mohd

AU - Muir, Kenneth

AU - Nevanlinna, Heli

AU - Newman, William

AU - Oosterwijk, Jan C

AU - Park, Sue K

AU - Peterlongo, Paolo

AU - Radice, Paolo

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K

AU - Shah, Mitul

AU - Sim, Xueling

AU - Southey, Melissa C

AU - Surowy, Harald

AU - Suvanto, Maija

AU - Tomlinson, Ian

AU - Torres, Diana

AU - Truong, Thérèse

AU - Van Asperen, Christi J.

AU - Waltes, Regina

AU - Wang, Qin

AU - Yang, Xiaohong R.

AU - Pharoah, Paul D.P.

AU - Schmidt, Marjanka K.

AU - Benitez, Javier

AU - Vroling, Bas

AU - Dunning, Alison M.

AU - Teo, Soo Hwang

AU - Kvist, Anders

AU - De la Hoya, Miguel

AU - Devilee, Peter

AU - Spurdle, Amanda B

AU - Vreeswijk, Maaike P G

AU - Easton, Douglas F

PY - 2021/9/15

Y1 - 2021/9/15

N2 - Background: Protein 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.Methods: Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), 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.Results: 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.Conclusions: 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.

AB - Background: Protein 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.Methods: Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), 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.Results: 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.Conclusions: 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.

UR - http://europepmc.org/abstract/PPR/PPR394729

U2 - 10.1101/2021.09.02.21262369

DO - 10.1101/2021.09.02.21262369

M3 - Article

SP - 1

EP - 36

JO - medRxiv

JF - medRxiv

ER -

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

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