A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2

Maria Zanti; Denise G. O'Mahony; Michael T. Parsons; Hongyan Li; Joe Dennis; Kristiina Aittomäkkiki; Irene L. Andrulis; Hoda Anton-Culver; Kristan J. Aronson; Annelie Augustinsson; Heiko Becher; Stig E. Bojesen; Manjeet K. Bolla; Hermann Brenner; Melissa A. Brown; Saundra S. Buys; Federico Canzian; Sandrine M. Caputo; Jose E. Castelao; Jenny Chang-Claude; Kamila Czene; Mary B. Daly; Arcangela De Nicolo; Peter Devilee; Thilo Dörk; Alison M. Dunning; Miriam Dwek; Diana M. Eccles; Christoph Engel; D. Gareth Evans; Peter A. Fasching; Manuela Gago-Dominguez; Montserrat García-Closas; José A. García-Sáenz; Aleksandra Gentry-Maharaj; Willemina R.R. Geurts-Giele; Graham G. Giles; Gord Glendon; Mark S. Goldberg; Encarna B. Gómez Garcia; Melanie Göendert; Pascal Guénel; Eric Hahnen; Christopher A. Haiman; Per Hall; Ute Hamann; Elaine F. Harkness; Frans B.L. Hogervorst; Antoinette Hollestelle; Reiner Hoppe; John L. Hopper; Claude Houdayer; Richard S. Houlston; Anthony Howell; Milena Jakimovska; Anna Jakubowska; Helena Jernström; Esther M. John; Rudolf Kaaks; Cari M. Kitahara; Stella Koutros; Peter Kraft; Vessela N. Kristensen; James V. Lacey; Diether Lambrechts; Melanie Léoné; Annika Lindblom; Jan Lubiski; Michael Lush; Arto Mannermaa; Mehdi Manoochehri; Siranoush Manoukian; Sara Margolin; Maria Elena Martinez; Usha Menon; Roger L. Milne; Alvaro N. Monteiro; Rachel A. Murphy; Susan L. Neuhausen; Heli Nevanlinna; William G. Newman; Kenneth Offit; Sue K. Park; Paul James; Paolo Peterlongo; Julian Peto; Dijana Plaseska-Karanfilska; Kevin Punie; Paolo Radice; Muhammad U. Rashid; Gad Rennert; Atocha Romero; Efraim H. Rosenberg; Emmanouil Saloustros; Dale P. Sandler; Marjanka K. Schmidt; Rita K. Schmutzler; Xiao Ou Shu; Jacques Simard; Melissa C. Southey; Jennifer Stone; Dominique Stoppa-Lyonnet; Rulla M. Tamimi; William J. Tapper; Jack A. Taylor; Soo Hwang Teo; Lauren R. Teras; Mary Beth Terry; Mads Thomassen; Melissa A. Troester; Celine M. Vachon; Ana Vega; Maaike P.G. Vreeswijk; Qin Wang; Barbara Wappenschmidt; Clarice R. Weinberg; Alicja Wolk; Wei Zheng; Bingjian Feng; Fergus J. Couch; Amanda B. Spurdle; Douglas F. Easton; David E. Goldgar; Kyriaki Michailidou

doi:10.1155/2023/9961341

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2

Maria Zanti, Denise G. O'Mahony, Michael T. Parsons, Hongyan Li, Joe Dennis, Kristiina Aittomäkkiki, Irene L. Andrulis, Hoda Anton-Culver, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Melissa A. Brown, Saundra S. Buys, Federico Canzian, Sandrine M. Caputo, Jose E. Castelao, Jenny Chang-ClaudeKamila Czene, Mary B. Daly, Arcangela De Nicolo, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Aleksandra Gentry-Maharaj, Willemina R.R. Geurts-Giele, Graham G. Giles, Gord Glendon, Mark S. Goldberg, Encarna B. Gómez Garcia, Melanie Göendert, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Frans B.L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Claude Houdayer, Richard S. Houlston, Anthony Howell, Milena Jakimovska, Anna Jakubowska, Helena Jernström, Esther M. John, Rudolf Kaaks, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, James V. Lacey, Diether Lambrechts, Melanie Léoné, Annika Lindblom, Jan Lubiski, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Usha Menon, Roger L. Milne, Alvaro N. Monteiro, Rachel A. Murphy, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Kenneth Offit, Sue K. Park, Paul James, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Kevin Punie, Paolo Radice, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Efraim H. Rosenberg, Emmanouil Saloustros, Dale P. Sandler, Marjanka K. Schmidt, Rita K. Schmutzler, Xiao Ou Shu, Jacques Simard, Melissa C. Southey, Jennifer Stone, Dominique Stoppa-Lyonnet, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Mary Beth Terry, Mads Thomassen, Melissa A. Troester, Celine M. Vachon, Ana Vega, Maaike P.G. Vreeswijk, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Alicja Wolk, Wei Zheng, Bingjian Feng, Fergus J. Couch, Amanda B. Spurdle, Douglas F. Easton, David E. Goldgar, Kyriaki Michailidou

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

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Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Original language	English
Article number	9961341
Journal	Human Mutation
Volume	2023
DOIs	https://doi.org/10.1155/2023/9961341
State	Published - 2023

Keywords

BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Case-Control Studies
Female
Genetic Predisposition to Disease
Genetic Testing/methods
Genetic Variation
Humans
Likelihood Functions
Penetrance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1155/2023/9961341

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Zanti, M., O'Mahony, D. G., Parsons, M. T., Li, H., Dennis, J., Aittomäkkiki, K., Andrulis, I. L., Anton-Culver, H., Aronson, K. J., Augustinsson, A., Becher, H., Bojesen, S. E., Bolla, M. K., Brenner, H., Brown, M. A., Buys, S. S., Canzian, F., Caputo, S. M., Castelao, J. E., ... Michailidou, K. (2023). A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2. Human Mutation, 2023, Article 9961341. https://doi.org/10.1155/2023/9961341

@article{72a5d4dc5d144c689fbe7ea77a639a4a,

title = "A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2",

abstract = "A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance. ",

keywords = "BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Case-Control Studies, Female, Genetic Predisposition to Disease, Genetic Testing/methods, Genetic Variation, Humans, Likelihood Functions, Penetrance",

author = "Maria Zanti and O'Mahony, {Denise G.} and Parsons, {Michael T.} and Hongyan Li and Joe Dennis and Kristiina Aittom{\"a}kkiki and Andrulis, {Irene L.} and Hoda Anton-Culver and Aronson, {Kristan J.} and Annelie Augustinsson and Heiko Becher and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Hermann Brenner and Brown, {Melissa A.} and Buys, {Saundra S.} and Federico Canzian and Caputo, {Sandrine M.} and Castelao, {Jose E.} and Jenny Chang-Claude and Kamila Czene and Daly, {Mary B.} and {De Nicolo}, Arcangela and Peter Devilee and Thilo D{\"o}rk and Dunning, {Alison M.} and Miriam Dwek and Eccles, {Diana M.} and Christoph Engel and {Gareth Evans}, D. and Fasching, {Peter A.} and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A.} and Aleksandra Gentry-Maharaj and Geurts-Giele, {Willemina R.R.} and Giles, {Graham G.} and Gord Glendon and Goldberg, {Mark S.} and {G{\'o}mez Garcia}, {Encarna B.} and Melanie G{\"o}endert and Pascal Gu{\'e}nel and Eric Hahnen and Haiman, {Christopher A.} and Per Hall and Ute Hamann and Harkness, {Elaine F.} and Hogervorst, {Frans B.L.} and Antoinette Hollestelle and Reiner Hoppe and Hopper, {John L.} and Claude Houdayer and Houlston, {Richard S.} and Anthony Howell and Milena Jakimovska and Anna Jakubowska and Helena Jernstr{\"o}m and John, {Esther M.} and Rudolf Kaaks and Kitahara, {Cari M.} and Stella Koutros and Peter Kraft and Kristensen, {Vessela N.} and Lacey, {James V.} and Diether Lambrechts and Melanie L{\'e}on{\'e} and Annika Lindblom and Jan Lubiski and Michael Lush and Arto Mannermaa and Mehdi Manoochehri and Siranoush Manoukian and Sara Margolin and Martinez, {Maria Elena} and Usha Menon and Milne, {Roger L.} and Monteiro, {Alvaro N.} and Murphy, {Rachel A.} and Neuhausen, {Susan L.} and Heli Nevanlinna and Newman, {William G.} and Kenneth Offit and Park, {Sue K.} and Paul James and Paolo Peterlongo and Julian Peto and Dijana Plaseska-Karanfilska and Kevin Punie and Paolo Radice and Rashid, {Muhammad U.} and Gad Rennert and Atocha Romero and Rosenberg, {Efraim H.} and Emmanouil Saloustros and Sandler, {Dale P.} and Schmidt, {Marjanka K.} and Schmutzler, {Rita K.} and Shu, {Xiao Ou} and Jacques Simard and Southey, {Melissa C.} and Jennifer Stone and Dominique Stoppa-Lyonnet and Tamimi, {Rulla M.} and Tapper, {William J.} and Taylor, {Jack A.} and Teo, {Soo Hwang} and Teras, {Lauren R.} and Terry, {Mary Beth} and Mads Thomassen and Troester, {Melissa A.} and Vachon, {Celine M.} and Ana Vega and Vreeswijk, {Maaike P.G.} and Qin Wang and Barbara Wappenschmidt and Weinberg, {Clarice R.} and Alicja Wolk and Wei Zheng and Bingjian Feng and Couch, {Fergus J.} and Spurdle, {Amanda B.} and Easton, {Douglas F.} and Goldgar, {David E.} and Kyriaki Michailidou",

year = "2023",

doi = "10.1155/2023/9961341",

language = "English",

volume = "2023",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

}

Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomäkkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Gareth Evans, D, Fasching, PA, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Gómez Garcia, EB, Göendert, M, Guénel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Jakimovska, M, Jakubowska, A, Jernström, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, JV, Lambrechts, D, Léoné, M, Lindblom, A, Lubiski, J, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, XO, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE & Michailidou, K 2023, 'A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2', Human Mutation, vol. 2023, 9961341. https://doi.org/10.1155/2023/9961341

TY - JOUR

T1 - A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants

T2 - Application to BRCA1 and BRCA2

AU - Zanti, Maria

AU - O'Mahony, Denise G.

AU - Parsons, Michael T.

AU - Li, Hongyan

AU - Dennis, Joe

AU - Aittomäkkiki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Aronson, Kristan J.

AU - Augustinsson, Annelie

AU - Becher, Heiko

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brenner, Hermann

AU - Brown, Melissa A.

AU - Buys, Saundra S.

AU - Canzian, Federico

AU - Caputo, Sandrine M.

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Czene, Kamila

AU - Daly, Mary B.

AU - De Nicolo, Arcangela

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dunning, Alison M.

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Engel, Christoph

AU - Gareth Evans, D.

AU - Fasching, Peter A.

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - García-Sáenz, José A.

AU - Gentry-Maharaj, Aleksandra

AU - Geurts-Giele, Willemina R.R.

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Goldberg, Mark S.

AU - Gómez Garcia, Encarna B.

AU - Göendert, Melanie

AU - Guénel, Pascal

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Hall, Per

AU - Hamann, Ute

AU - Harkness, Elaine F.

AU - Hogervorst, Frans B.L.

AU - Hollestelle, Antoinette

AU - Hoppe, Reiner

AU - Hopper, John L.

AU - Houdayer, Claude

AU - Houlston, Richard S.

AU - Howell, Anthony

AU - Jakimovska, Milena

AU - Jakubowska, Anna

AU - Jernström, Helena

AU - John, Esther M.

AU - Kaaks, Rudolf

AU - Kitahara, Cari M.

AU - Koutros, Stella

AU - Kraft, Peter

AU - Kristensen, Vessela N.

AU - Lacey, James V.

AU - Lambrechts, Diether

AU - Léoné, Melanie

AU - Lindblom, Annika

AU - Lubiski, Jan

AU - Lush, Michael

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Martinez, Maria Elena

AU - Menon, Usha

AU - Milne, Roger L.

AU - Monteiro, Alvaro N.

AU - Murphy, Rachel A.

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Newman, William G.

AU - Offit, Kenneth

AU - Park, Sue K.

AU - James, Paul

AU - Peterlongo, Paolo

AU - Peto, Julian

AU - Plaseska-Karanfilska, Dijana

AU - Punie, Kevin

AU - Radice, Paolo

AU - Rashid, Muhammad U.

AU - Rennert, Gad

AU - Romero, Atocha

AU - Rosenberg, Efraim H.

AU - Saloustros, Emmanouil

AU - Sandler, Dale P.

AU - Schmidt, Marjanka K.

AU - Schmutzler, Rita K.

AU - Shu, Xiao Ou

AU - Simard, Jacques

AU - Southey, Melissa C.

AU - Stone, Jennifer

AU - Stoppa-Lyonnet, Dominique

AU - Tamimi, Rulla M.

AU - Tapper, William J.

AU - Taylor, Jack A.

AU - Teo, Soo Hwang

AU - Teras, Lauren R.

AU - Terry, Mary Beth

AU - Thomassen, Mads

AU - Troester, Melissa A.

AU - Vachon, Celine M.

AU - Vega, Ana

AU - Vreeswijk, Maaike P.G.

AU - Wang, Qin

AU - Wappenschmidt, Barbara

AU - Weinberg, Clarice R.

AU - Wolk, Alicja

AU - Zheng, Wei

AU - Feng, Bingjian

AU - Couch, Fergus J.

AU - Spurdle, Amanda B.

AU - Easton, Douglas F.

AU - Goldgar, David E.

AU - Michailidou, Kyriaki

PY - 2023

Y1 - 2023

N2 - A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

AB - A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Testing/methods

KW - Genetic Variation

KW - Humans

KW - Likelihood Functions

KW - Penetrance

UR - http://www.scopus.com/inward/record.url?scp=85176617210&partnerID=8YFLogxK

U2 - 10.1155/2023/9961341

DO - 10.1155/2023/9961341

M3 - Article

C2 - 38725546

AN - SCOPUS:85176617210

SN - 1059-7794

VL - 2023

JO - Human Mutation

JF - Human Mutation

M1 - 9961341

ER -

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2

Abstract

Keywords

UN SDGs

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