A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2
- Author(s)
- Zanti, M; O'Mahony, DG; Parsons, MT; Li, H; Dennis, J; Aittomakkiki, 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; GC-HBOC study Collaborators; Czene, K; Daly, MB; De Nicolo, A; Devilee, P; Dork, T; Dunning, AM; Dwek, M; Eccles, DM; Engel, C; Evans, DG; Fasching, PA; Gago-Dominguez, M; Garcia-Closas, M; Garcia-Saenz, JA; Gentry-Maharaj, A; Geurts-Giele, WRR; Giles, GG; Glendon, G; Goldberg, MS; Gomez Garcia, EB; Guendert, M; Guenel, 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; ABCTB Investigators; Jakimovska, M; Jakubowska, A; Jernstrom, H; John, EM; Kaaks, R; Kitahara, CM; Koutros, S; Kraft, P; Kristensen, VN; Lacey, JV; Lambrechts, D; Leone, M; Lindblom, A; Lubinski, 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;
- Journal Title
- Human Mutation
- Publication Type
- Research article
- 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
- Humans; Case-Control Studies; *BRCA2 Protein/genetics; *Genetic Predisposition to Disease; Female; *BRCA1 Protein/genetics; *Breast Neoplasms/genetics; Likelihood Functions; Genetic Variation; Penetrance; Genetic Testing/methods; Acmg/amp; Brca; Ps4; Vus; case-control; likelihood ratio; variant classification
- Department(s)
- Familial Cancer Centre
- PubMed ID
- 38725546
- Publisher's Version
- https://doi.org/10.1155/2023/9961341
- Open Access at Publisher's Site
https://doi.org/10.1155/2023/9961341- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-08-20 06:18:12
Last Modified: 2024-08-20 06:56:39