A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2
Authors: Zanti Maria , O'Mahony Denise G. , Parsons Michael T. , Li Hongyan , Dennis Joe , Aittomäkkiki Kristiina , Andrulis Irene L. , Anton-Culver Hoda , Aronson Kristan J. , Augustinsson Annelie , Becher Heiko , Bojesen Stig E. , Bolla Manjeet K. , Brenner Hermann , Brown Melissa A. , Buys Saundra S. , Canzian Federico , Caputo Sandrine M. , Castelao Jose E. , Chang-Claude Jenny , GC-HBOC study Collaborators  , Czene Kamila , Daly Mary B. , De Nicolo Arcangela , Devilee Peter , Dörk Thilo , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Engel Christoph , Evans D. Gareth , Fasching Peter A. , Gago-Dominguez Manuela , García-Closas Montserrat , García-Sáenz José A. , Gentry-Maharaj Aleksandra , Geurts - Giele Willemina R. R. , Giles Graham G. , Glendon Gord , Goldberg Mark S. , Gómez Garcia Encarna B. , Güendert Melanie , Guénel Pascal , Hahnen Eric , Haiman Christopher A. , Hall Per , Hamann Ute , Harkness Elaine F. , Hogervorst Frans B. L. , Hollestelle Antoinette , Hoppe Reiner , Hopper John L. , Houdayer Claude , Houlston Richard S. , Howell Anthony , ABCTB Investigators  , Jakimovska Milena , Jakubowska Anna , Jernström Helena , John Esther M. , Kaaks Rudolf , Kitahara Cari M. , Koutros Stella , Kraft Peter , Kristensen Vessela N. , Lacey James V. , Lambrechts Diether , Léoné Melanie , Lindblom Annika , Lubiński Jan , Lush Michael , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martinez Maria Elena , Menon Usha , Milne Roger L. , Monteiro Alvaro N. , Murphy Rachel A. , Neuhausen Susan L. , Nevanlinna Heli , Newman William G. , Offit Kenneth , Park Sue K. , James Paul , Peterlongo Paolo , Peto Julian , Plaseska-Karanfilska Dijana , Punie Kevin , Radice Paolo , Rashid Muhammad U. , Rennert Gad , Romero Atocha , Rosenberg Efraim H. , Saloustros Emmanouil , Sandler Dale P. , Schmidt Marjanka K. , Schmutzler Rita K. , Shu Xiao-Ou , Simard Jacques , Southey Melissa C. , Stone Jennifer , Stoppa-Lyonnet Dominique , Tamimi Rulla M. , Tapper William J. , Taylor Jack A. , Teo Soo Hwang , Teras Lauren R. , Terry Mary Beth , Thomassen Mads , Troester Melissa A. , Vachon Celine M. , Vega Ana , Vreeswijk Maaike P. G. , Wang Qin , Wappenschmidt Barbara , Weinberg Clarice R. , Wolk Alicja , Zheng Wei , Feng Bingjian , Couch Fergus J. , Spurdle Amanda B. , Easton Douglas F. , Goldgar David E. , Michailidou Kyriaki 
Published: September 2023

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 analysis 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 with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.