No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing

Douglas F Easton; Fabienne Lesueur; Brennan Decker; Kyriaki Michailidou; Jun Li; Jamie Allen; Craig Luccarini; Karen A Pooley; Mitul Shah; Manjeet K. Bolla; Qin Wang; Joe Dennis; Jamil Ahmad; Ella R Thompson; Francesca Damiola; Maroulio Pertesi; Catherine Voegele; Noura Mebirouk; Nivonirina Robinot; Geoffroy Durand; Nathalie Forey; Robert N. Luben; Shahana Ahmed; Kristiina Aittomäki; Hoda Anton-Culver; Volker Arndt; Caroline Baynes; Matthias W Beckman; Javier Benitez; David Berg; William J. Blot; Natalia V. Bogdanova; Stig E Bojesen; Hermann Brenner; Jenny Chang-Claude; Kee Seng Chia; Ji Yeob Choi; Don M. Conroy; Angela Cox; Simon S Cross; Kamila Czene; Hatef Darabi; Peter Devilee; Mikael Eriksson; Peter A. Fasching; Jonine D Figueroa; Henrik Flyger; Florentia Fostira; Montserrat García-Closas; Graham G. Giles; Gord Glendon; Anna González-Neira; Pascal Guénel; Christopher A Haiman; Per Hall; Steven N. Hart; Mikael Hartman; Maartje J Hooning; Chia-Ni Hsiung; Hidemi Ito; Anna Jakubowska; Paul A. James; Esther M. John; Nichola Johnson; Michael Jones; Maria Kabisch; Daehee Kang; Veli-Matti Kosma; Vessela Kristensen; Diether Lambrechts; Na Li; Eija Myöhänen; Helena Kemiläinen; Annika Lindblom; Jirong Long; Artitaya Lophatananon; Jan Lubinski; Arto Mannermaa; Siranoush Manoukian; Sara Margolin; Keitaro Matsuo; Alfons Meindl; Gillian W E Mitchell; Kenneth Muir; Ines Nevelsteen; Ans M W van den Ouweland; Paolo Peterlongo; Sze Yee Phuah; Katri Pylkäs; Simone M Rowley; Suleeporn Sangrajrang; Rita K. Schmutzler; Chen-Yang Shen; Xiao-Ou Shu; Melissa C. Southey; Harald Surowy; Anthony J Swerdlow; Soo-Hwang Teo; Rob A.E.M. Tollenaar; Ian P Tomlinson; Diana Torres; Thérèse Truong; Celine M Vachon; Senno Verhoef; Michelle W. Wong-Brown; Wei Zheng; Ying Zheng; Heli Nevanlinna; Rodney J. Scott; Irene L Andrulis; Anna H Wu; John L. Hopper; Fergus J Couch; Robert Winqvist; Barbara Burwinkel; Elinor J Sawyer; Marjanka K. Schmidt; Anja Rudolph; Thilo Dörk; Hiltrud Brauch; Ute Hamann; Susan L Neuhausen; Roger L Milne; Olivia Fletcher; Paul D P Pharoah; Ian G. Campbell; Alison M Dunning; Florence L. Le Calvez-Kelm; David E. Goldgar; Sean V. Tavtigian; Georgia Chenevix-Trench; Kristine Kleivi; Lars Ottestad; Rolf Kåresen; Anita Langerød; Ellen Schlichting; Marit Muri Holmen; Toril Sauer; Vilde D. Haakensen; Olav Engebråten; Bjørn Naume; Cecile E. Kiserud; Kristin V. Reinertsen; Åslaug Helland; Margit Riis; Ida Bukholm; Per Eystein Lønning; Silje Nord; Grethe I.Grenaker Alnæs; Australian Ovarian Cancer Study Group (AOCS); kConFab Investigators; Lifepool Investigators; NBCS Investigators

doi:10.1136/jmedgenet-2015-103529

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing

Douglas F Easton, Fabienne Lesueur, Brennan Decker, Kyriaki Michailidou, Jun Li, Jamie Allen, Craig Luccarini, Karen A Pooley, Mitul Shah, Manjeet K. Bolla, Qin Wang, Joe Dennis, Jamil Ahmad, Ella R Thompson, Francesca Damiola, Maroulio Pertesi, Catherine Voegele, Noura Mebirouk, Nivonirina Robinot, Geoffroy DurandNathalie Forey, Robert N. Luben, Shahana Ahmed, Kristiina Aittomäki, Hoda Anton-Culver, Volker Arndt, Caroline Baynes, Matthias W Beckman, Javier Benitez, David Berg, William J. Blot, Natalia V. Bogdanova, Stig E Bojesen, Hermann Brenner, Jenny Chang-Claude, Kee Seng Chia, Ji Yeob Choi, Don M. Conroy, Angela Cox, Simon S Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Mikael Eriksson, Peter A. Fasching, Jonine D Figueroa, Henrik Flyger, Florentia Fostira, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Anna González-Neira, Pascal Guénel, Christopher A Haiman, Per Hall, Steven N. Hart, Mikael Hartman, Maartje J Hooning, Chia-Ni Hsiung, Hidemi Ito, Anna Jakubowska, Paul A. James, Esther M. John, Nichola Johnson, Michael Jones, Maria Kabisch, Daehee Kang, Veli-Matti Kosma, Vessela Kristensen, Diether Lambrechts, Na Li, Eija Myöhänen, Helena Kemiläinen, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Keitaro Matsuo, Alfons Meindl, Gillian W E Mitchell, Kenneth Muir, Ines Nevelsteen, Ans M W van den Ouweland, Paolo Peterlongo, Sze Yee Phuah, Katri Pylkäs, Simone M Rowley, Suleeporn Sangrajrang, Rita K. Schmutzler, Chen-Yang Shen, Xiao-Ou Shu, Melissa C. Southey, Harald Surowy, Anthony J Swerdlow, Soo-Hwang Teo, Rob A.E.M. Tollenaar, Ian P Tomlinson, Diana Torres, Thérèse Truong, Celine M Vachon, Senno Verhoef, Michelle W. Wong-Brown, Wei Zheng, Ying Zheng, Heli Nevanlinna, Rodney J. Scott, Irene L Andrulis, Anna H Wu, John L. Hopper, Fergus J Couch, Robert Winqvist, Barbara Burwinkel, Elinor J Sawyer, Marjanka K. Schmidt, Anja Rudolph, Thilo Dörk, Hiltrud Brauch, Ute Hamann, Susan L Neuhausen, Roger L Milne, Olivia Fletcher, Paul D P Pharoah, Ian G. Campbell, Alison M Dunning, Florence L. Le Calvez-Kelm, David E. Goldgar, Sean V. Tavtigian, Georgia Chenevix-Trench, Kristine Kleivi, Lars Ottestad, Rolf Kåresen, Anita Langerød, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde D. Haakensen, Olav Engebråten, Bjørn Naume, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Ida Bukholm, Per Eystein Lønning, Silje Nord, Grethe I.Grenaker Alnæs, Australian Ovarian Cancer Study Group (AOCS), kConFab Investigators, Lifepool Investigators, NBCS Investigators

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

89 Citations (Scopus)

Abstract

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p. Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p. Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Original language	English
Pages (from-to)	298-309
Number of pages	12
Journal	Journal of Medical Genetics
Volume	53
Issue number	5
DOIs	https://doi.org/10.1136/jmedgenet-2015-103529
Publication status	Published - 26 Feb 2016
Externally published	Yes

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Easton, D. F., Lesueur, F., Decker, B., Michailidou, K., Li, J., Allen, J., Luccarini, C., Pooley, K. A., Shah, M., Bolla, M. K., Wang, Q., Dennis, J., Ahmad, J., Thompson, E. R., Damiola, F., Pertesi, M., Voegele, C., Mebirouk, N., Robinot, N., ... NBCS Investigators (2016). No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing. Journal of Medical Genetics, 53(5), 298-309. https://doi.org/10.1136/jmedgenet-2015-103529

@article{c3d16114f4b34ae791d6228d466cad4f,

title = "No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing",

abstract = "Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p. Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p. Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.",

author = "Easton, {Douglas F} and Fabienne Lesueur and Brennan Decker and Kyriaki Michailidou and Jun Li and Jamie Allen and Craig Luccarini and Pooley, {Karen A} and Mitul Shah and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Jamil Ahmad and Thompson, {Ella R} and Francesca Damiola and Maroulio Pertesi and Catherine Voegele and Noura Mebirouk and Nivonirina Robinot and Geoffroy Durand and Nathalie Forey and Luben, {Robert N.} and Shahana Ahmed and Kristiina Aittom{\"a}ki and Hoda Anton-Culver and Volker Arndt and Caroline Baynes and Beckman, {Matthias W} and Javier Benitez and David Berg and Blot, {William J.} and Bogdanova, {Natalia V.} and Bojesen, {Stig E} and Hermann Brenner and Jenny Chang-Claude and Chia, {Kee Seng} and Choi, {Ji Yeob} and Conroy, {Don M.} and Angela Cox and Cross, {Simon S} and Kamila Czene and Hatef Darabi and Peter Devilee and Mikael Eriksson and Fasching, {Peter A.} and Figueroa, {Jonine D} and Henrik Flyger and Florentia Fostira and Montserrat Garc{\'i}a-Closas and Giles, {Graham G.} and Gord Glendon and Anna Gonz{\'a}lez-Neira and Pascal Gu{\'e}nel and Haiman, {Christopher A} and Per Hall and Hart, {Steven N.} and Mikael Hartman and Hooning, {Maartje J} and Chia-Ni Hsiung and Hidemi Ito and Anna Jakubowska and James, {Paul A.} and John, {Esther M.} and Nichola Johnson and Michael Jones and Maria Kabisch and Daehee Kang and Veli-Matti Kosma and Vessela Kristensen and Diether Lambrechts and Na Li and Eija My{\"o}h{\"a}nen and Helena Kemil{\"a}inen and Annika Lindblom and Jirong Long and Artitaya Lophatananon and Jan Lubinski and Arto Mannermaa and Siranoush Manoukian and Sara Margolin and Keitaro Matsuo and Alfons Meindl and Mitchell, {Gillian W E} and Kenneth Muir and Ines Nevelsteen and {van den Ouweland}, {Ans M W} and Paolo Peterlongo and Phuah, {Sze Yee} and Katri Pylk{\"a}s and Rowley, {Simone M} and Suleeporn Sangrajrang and Schmutzler, {Rita K.} and Chen-Yang Shen and Xiao-Ou Shu and Southey, {Melissa C.} and Harald Surowy and Swerdlow, {Anthony J} and Soo-Hwang Teo and Tollenaar, {Rob A.E.M.} and Tomlinson, {Ian P} and Diana Torres and Th{\'e}r{\`e}se Truong and Vachon, {Celine M} and Senno Verhoef and Wong-Brown, {Michelle W.} and Wei Zheng and Ying Zheng and Heli Nevanlinna and Scott, {Rodney J.} and Andrulis, {Irene L} and Wu, {Anna H} and Hopper, {John L.} and Couch, {Fergus J} and Robert Winqvist and Barbara Burwinkel and Sawyer, {Elinor J} and Schmidt, {Marjanka K.} and Anja Rudolph and Thilo D{\"o}rk and Hiltrud Brauch and Ute Hamann and Neuhausen, {Susan L} and Milne, {Roger L} and Olivia Fletcher and Pharoah, {Paul D P} and Campbell, {Ian G.} and Dunning, {Alison M} and {Le Calvez-Kelm}, {Florence L.} and Goldgar, {David E.} and Tavtigian, {Sean V.} and Georgia Chenevix-Trench and Kristine Kleivi and Lars Ottestad and Rolf K{\aa}resen and Anita Langer{\o}d and Ellen Schlichting and Holmen, {Marit Muri} and Toril Sauer and Haakensen, {Vilde D.} and Olav Engebr{\aa}ten and Bj{\o}rn Naume and Kiserud, {Cecile E.} and Reinertsen, {Kristin V.} and {\AA}slaug Helland and Margit Riis and Ida Bukholm and L{\o}nning, {Per Eystein} and Silje Nord and Aln{\ae}s, {Grethe I.Grenaker} and {Australian Ovarian Cancer Study Group (AOCS)} and {kConFab Investigators} and {Lifepool Investigators} and {NBCS Investigators}",

year = "2016",

month = feb,

day = "26",

doi = "10.1136/jmedgenet-2015-103529",

language = "English",

volume = "53",

pages = "298--309",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ",

number = "5",

}

Easton, DF, Lesueur, F, Decker, B, Michailidou, K, Li, J, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Dennis, J, Ahmad, J, Thompson, ER, Damiola, F, Pertesi, M, Voegele, C, Mebirouk, N, Robinot, N, Durand, G, Forey, N, Luben, RN, Ahmed, S, Aittomäki, K, Anton-Culver, H, Arndt, V, Baynes, C, Beckman, MW, Benitez, J, Berg, D, Blot, WJ, Bogdanova, NV, Bojesen, SE, Brenner, H, Chang-Claude, J, Chia, KS, Choi, JY, Conroy, DM, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Eriksson, M, Fasching, PA, Figueroa, JD, Flyger, H, Fostira, F, García-Closas, M, Giles, GG, Glendon, G, González-Neira, A, Guénel, P, Haiman, CA, Hall, P, Hart, SN, Hartman, M, Hooning, MJ, Hsiung, C-N, Ito, H, Jakubowska, A, James, PA, John, EM, Johnson, N, Jones, M, Kabisch, M, Kang, D, Kosma, V-M, Kristensen, V, Lambrechts, D, Li, N, Myöhänen, E, Kemiläinen, H, Lindblom, A, Long, J, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Meindl, A, Mitchell, GWE, Muir, K, Nevelsteen, I, van den Ouweland, AMW, Peterlongo, P, Phuah, SY, Pylkäs, K, Rowley, SM, Sangrajrang, S, Schmutzler, RK, Shen, C-Y, Shu, X-O, Southey, MC, Surowy, H, Swerdlow, AJ, Teo, S-H, Tollenaar, RAEM, Tomlinson, IP, Torres, D, Truong, T, Vachon, CM, Verhoef, S, Wong-Brown, MW, Zheng, W, Zheng, Y, Nevanlinna, H, Scott, RJ, Andrulis, IL, Wu, AH, Hopper, JL, Couch, FJ, Winqvist, R, Burwinkel, B, Sawyer, EJ, Schmidt, MK, Rudolph, A, Dörk, T, Brauch, H, Hamann, U, Neuhausen, SL, Milne, RL, Fletcher, O, Pharoah, PDP, Campbell, IG, Dunning, AM, Le Calvez-Kelm, FL, Goldgar, DE, Tavtigian, SV, Chenevix-Trench, G, Kleivi, K, Ottestad, L, Kåresen, R, Langerød, A, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, VD, Engebråten, O, Naume, B, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Bukholm, I, Lønning, PE, Nord, S, Alnæs, GIG, Australian Ovarian Cancer Study Group (AOCS), kConFab Investigators, Lifepool Investigators & NBCS Investigators 2016, 'No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing', Journal of Medical Genetics, vol. 53, no. 5, pp. 298-309. https://doi.org/10.1136/jmedgenet-2015-103529

TY - JOUR

T1 - No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk

T2 - Implications for gene panel testing

AU - Easton, Douglas F

AU - Lesueur, Fabienne

AU - Decker, Brennan

AU - Michailidou, Kyriaki

AU - Li, Jun

AU - Allen, Jamie

AU - Luccarini, Craig

AU - Pooley, Karen A

AU - Shah, Mitul

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Ahmad, Jamil

AU - Thompson, Ella R

AU - Damiola, Francesca

AU - Pertesi, Maroulio

AU - Voegele, Catherine

AU - Mebirouk, Noura

AU - Robinot, Nivonirina

AU - Durand, Geoffroy

AU - Forey, Nathalie

AU - Luben, Robert N.

AU - Ahmed, Shahana

AU - Aittomäki, Kristiina

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Baynes, Caroline

AU - Beckman, Matthias W

AU - Benitez, Javier

AU - Berg, David

AU - Blot, William J.

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

AU - Chia, Kee Seng

AU - Choi, Ji Yeob

AU - Conroy, Don M.

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Devilee, Peter

AU - Eriksson, Mikael

AU - Fasching, Peter A.

AU - Figueroa, Jonine D

AU - Flyger, Henrik

AU - Fostira, Florentia

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - Glendon, Gord

AU - González-Neira, Anna

AU - Guénel, Pascal

AU - Haiman, Christopher A

AU - Hall, Per

AU - Hart, Steven N.

AU - Hartman, Mikael

AU - Hooning, Maartje J

AU - Hsiung, Chia-Ni

AU - Ito, Hidemi

AU - Jakubowska, Anna

AU - James, Paul A.

AU - John, Esther M.

AU - Johnson, Nichola

AU - Jones, Michael

AU - Kabisch, Maria

AU - Kang, Daehee

AU - Kosma, Veli-Matti

AU - Kristensen, Vessela

AU - Lambrechts, Diether

AU - Li, Na

AU - Myöhänen, Eija

AU - Kemiläinen, Helena

AU - Lindblom, Annika

AU - Long, Jirong

AU - Lophatananon, Artitaya

AU - Lubinski, Jan

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Matsuo, Keitaro

AU - Meindl, Alfons

AU - Mitchell, Gillian W E

AU - Muir, Kenneth

AU - Nevelsteen, Ines

AU - van den Ouweland, Ans M W

AU - Peterlongo, Paolo

AU - Phuah, Sze Yee

AU - Pylkäs, Katri

AU - Rowley, Simone M

AU - Sangrajrang, Suleeporn

AU - Schmutzler, Rita K.

AU - Shen, Chen-Yang

AU - Shu, Xiao-Ou

AU - Southey, Melissa C.

AU - Surowy, Harald

AU - Swerdlow, Anthony J

AU - Teo, Soo-Hwang

AU - Tollenaar, Rob A.E.M.

AU - Tomlinson, Ian P

AU - Torres, Diana

AU - Truong, Thérèse

AU - Vachon, Celine M

AU - Verhoef, Senno

AU - Wong-Brown, Michelle W.

AU - Zheng, Wei

AU - Zheng, Ying

AU - Nevanlinna, Heli

AU - Scott, Rodney J.

AU - Andrulis, Irene L

AU - Wu, Anna H

AU - Hopper, John L.

AU - Couch, Fergus J

AU - Winqvist, Robert

AU - Burwinkel, Barbara

AU - Sawyer, Elinor J

AU - Schmidt, Marjanka K.

AU - Rudolph, Anja

AU - Dörk, Thilo

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Neuhausen, Susan L

AU - Milne, Roger L

AU - Fletcher, Olivia

AU - Pharoah, Paul D P

AU - Campbell, Ian G.

AU - Dunning, Alison M

AU - Le Calvez-Kelm, Florence L.

AU - Goldgar, David E.

AU - Tavtigian, Sean V.

AU - Chenevix-Trench, Georgia

AU - Kleivi, Kristine

AU - Ottestad, Lars

AU - Kåresen, Rolf

AU - Langerød, Anita

AU - Schlichting, Ellen

AU - Holmen, Marit Muri

AU - Sauer, Toril

AU - Haakensen, Vilde D.

AU - Engebråten, Olav

AU - Naume, Bjørn

AU - Kiserud, Cecile E.

AU - Reinertsen, Kristin V.

AU - Helland, Åslaug

AU - Riis, Margit

AU - Bukholm, Ida

AU - Lønning, Per Eystein

AU - Nord, Silje

AU - Alnæs, Grethe I.Grenaker

AU - Australian Ovarian Cancer Study Group (AOCS)

AU - kConFab Investigators

AU - Lifepool Investigators

AU - NBCS Investigators

PY - 2016/2/26

Y1 - 2016/2/26

N2 - Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p. Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p. Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

AB - Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p. Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p. Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

UR - http://www.scopus.com/inward/record.url?scp=84959299225&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2015-103529

DO - 10.1136/jmedgenet-2015-103529

M3 - Article

C2 - 26921362

AN - SCOPUS:84959299225

SN - 0022-2593

VL - 53

SP - 298

EP - 309

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 5

ER -

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing

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