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

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 ca...

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Autores: 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 Fernández, José Esteban, Chang-Claude, J., Czene, K., Daly, M.B., De Nicolo, A., Devilee, P., Dörk, T., Dunning, A.M., Dwek, M., Eccles, D.M., Engel, C., Gareth Evans, D., Fasching, P.A., Gago Dominguez, Manuela, García-Closas, M., García-Sáenz, J.A., Gentry-Maharaj, A., Geurts-Giele, W.R.R., Giles, G.G., Glendon, G., Goldberg, M.S., Gómez Garcia, E.B., Göendert, M., Guénel, P., Hahnen, E., Haiman, C.A., Hall, P., Hamann, U., Harkness, E.F., Hogervorst, F.B.L., Hollestelle, A., Hoppe, R., Hopper, J.L., Houdayer, C., Houlston, R.S., Howell, A., Jakimovska, M., Jakubowska, A., Jernström, H., John, E.M., Kaaks, R., Kitahara, C.M., Koutros, S., Kraft, P., Kristensen, V.N., Lacey, J.V., Lambrechts, D., Léoné, M., Lindblom, A., Lubiski, J., Lush, M., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Menon, U., Milne, R.L., Monteiro, A.N., Murphy, R.A., Neuhausen, S.L., Nevanlinna, H., Newman, W.G., Offit, K., Park, S.K., James, P., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Punie, K., Radice, P., Rashid, M.U., Rennert, G., Romero, A., Rosenberg, E.H., Saloustros, E., Sandler, D.P., Schmidt, M.K., Schmutzler, R.K., Shu, X.-O., Simard, J., Southey, M.C., Stone, J., Stoppa-Lyonnet, D., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teo, S.H., Teras, L.R., Terry, M.B., Thomassen, M., Troester, M.A., Vachon, C.M., Vega Gliemmo, Ana, Vreeswijk, M.P.G., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Wolk, A., Zheng, W., Feng, B., Couch, F.J., Spurdle, A.B., Easton, D.F., Goldgar, D.E., Michailidou, K.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/20981
Acceso en línea:https://portalcientifico.sergas.gal//documentos/6562086df2e9e72161e163e8
http://hdl.handle.net/20.500.11940/20981
Access Level:acceso abierto
Palabra clave:Humans
Case-Control Studies
BRCA2 Protein
Genetic Predisposition to Disease
Female
BRCA1 Protein
Breast Neoplasms
Likelihood Functions
Genetic Variation
Penetrance
Genetic Testing
AS Vigo
CHUVI
AS Santiago
IDIS
FPGMX
Descripción
Sumario: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.

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