A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2.
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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 PG
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
;
(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.
pp. 1-17.
ISSN 1059-7794
DOI: 10.1155/2023/9961341
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.
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