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

Details

• Alternative Title:
  Hum Mutat
• Personal Author:
  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 ; 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. ; Garcia, Encarna B. Gómez ; 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 ; 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
• Corporate Authors:
  GC-HBOC study Collaborators ; ABCTB Investigators
• Description:
  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 | and | 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 |, | and other high-risk genes with known penetrance.
• Subjects:
  BRCA1 Protein BRCA2 Protein Breast Neoplasms Case-Control Studies Female Genetic Predisposition To Disease Genetic Testing Genetic Variation Humans Likelihood Functions Penetrance

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• Keywords:
  ACMG/AMP BRCA Case-control Likelihood Ratio PS4 Variant Classification VUS
• Source:
  Hum Mutat. 2023
• Pubmed ID:
  38725546
• Pubmed Central ID:
  PMC11080979
• Document Type:
  Journal Article
• Funding:
  R01 CA176785/CA/NCI NIH HHSUnited States/ ; NU58DP006344/DP/NCCDPHP CDC HHSUnited States/ ; HHSN261201800015I/CA/NCI NIH HHSUnited States/ ; K07 CA092044/CA/NCI NIH HHSUnited States/ ; R01 CA128978/CA/NCI NIH HHSUnited States/ ; P50 CA116201/CA/NCI NIH HHSUnited States/ ; HHSN261201800015C/CA/NCI NIH HHSUnited States/ ; HHSN261201800009I/CA/NCI NIH HHSUnited States/ ; UM1 CA164917/CA/NCI NIH HHSUnited States/ ; U01 CA199277/CA/NCI NIH HHSUnited States/ ; U01 CA179715/CA/NCI NIH HHSUnited States/ ; R01 CA128931/CA/NCI NIH HHSUnited States/ ; HHSN261201800032C/CA/NCI NIH HHSUnited States/ ; U54 CA156733/CA/NCI NIH HHSUnited States/ ; HHSN261201800009C/CA/NCI NIH HHSUnited States/ ; Z01 CP010119/ImNIH/Intramural NIH HHSUnited States/ ; UM1 CA164973/CA/NCI NIH HHSUnited States/ ; P01 CA087969/CA/NCI NIH HHSUnited States/ ; UM1 CA164920/CA/NCI NIH HHSUnited States/ ; R01 CA097396/CA/NCI NIH HHSUnited States/ ; UM1 CA176726/CA/NCI NIH HHSUnited States/ ; Z01 ES049030/ImNIH/Intramural NIH HHSUnited States/ ; R01 CA058860/CA/NCI NIH HHSUnited States/ ; P50 CA058223/CA/NCI NIH HHSUnited States/ ; R01 CA100374/CA/NCI NIH HHSUnited States/ ; U19 CA148537/CA/NCI NIH HHSUnited States/ ; R01 CA116167/CA/NCI NIH HHSUnited States/ ; R01 CA177150/CA/NCI NIH HHSUnited States/ ; R01 CA063464/CA/NCI NIH HHSUnited States/ ; UM1 CA186107/CA/NCI NIH HHSUnited States/ ; P30 CA023100/CA/NCI NIH HHSUnited States/ ; U01 CA063464/CA/NCI NIH HHSUnited States/ ; R01 CA077398/CA/NCI NIH HHSUnited States/ ; R01 CA054281/CA/NCI NIH HHSUnited States/ ; R01 CA132839/CA/NCI NIH HHSUnited States/ ; P30 CA068485/CA/NCI NIH HHSUnited States/ ; U01 CA058860/CA/NCI NIH HHSUnited States/ ; U01 CA164920/CA/NCI NIH HHSUnited States/ ; R35 CA253187/CA/NCI NIH HHSUnited States/ ; U19 CA148112/CA/NCI NIH HHSUnited States/ ; HHSN261201800032I/CA/NCI NIH HHSUnited States/ ; U01 CA098758/CA/NCI NIH HHSUnited States/ ; Z01 ES044005/ImNIH/Intramural NIH HHSUnited States/ ; U19 CA148065/CA/NCI NIH HHSUnited States/ ; P30 CA033572/CA/NCI NIH HHSUnited States/ ; Z01 ES049033/ImNIH/Intramural NIH HHSUnited States/ ; R01 CA192393/CA/NCI NIH HHSUnited States/ ; R37 CA054281/CA/NCI NIH HHSUnited States/ ; U01 CA164973/CA/NCI NIH HHSUnited States/ ; R01 CA140286/CA/NCI NIH HHSUnited States/
• Volume:
  2023
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:832e496b603508ecf7ad8f410cf9182d06c14d98f83309ed585684efd9104496
• Download URL:
  https://stacks.cdc.gov/view/cdc/156326/cdc_156326_DS1.pdf
• File Type:
  [PDF - 681.42 KB ]