@article{b8f976d4bdf14d70814108fdd4c451a1,
title = "Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification",
abstract = "The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.",
keywords = "BRCA1, BRCA2, classification, clinical, multifactorial, quantitative, uncertain significance, variant, SEQUENCE VARIANTS, BREAST-CANCER, UNCERTAIN SIGNIFICANCE, INTEGRATED EVALUATION, FUNCTIONAL ASSAYS, SPLICING ANALYSIS, GUIDELINES, CLINGEN, OVARIAN, RISKS",
author = "Parsons, {Michael T.} and Emma Tudini and Hongyan Li and Eric Hahnen and Barbara Wappenschmidt and Lidia Feliubadalo and Aalfs, {Cora M.} and Simona Agata and Kristiina Aittomaki and Elisa Alducci and {Concepcion Alonso-Cerezo}, Maria and Norbert Arnold and Bernd Auber and Rachel Austin and Jacopo Azzollini and Judith Balmana and Elena Barbieri and Bartram, {Claus R.} and Ana Blanco and Britta Bluemcke and Sandra Bonache and Bernardo Bonanni and Ake Borg and Beatrice Bortesi and Joan Brunet and Carla Bruzzone and Karolin Bucksch and Giulia Cagnoli and Trinidad Caldes and Almuth Caliebe and Caligo, {Maria A.} and Mariarosaria Calvello and Capone, {Gabriele L.} and Caputo, {Sandrine M.} and Ileana Carnevali and Estela Carrasco and Virginie Caux-Moncoutier and Pietro Cavalli and Giulia Cini and Clarke, {Edward M.} and Paola Concolino and Cops, {Elisa J.} and Laura Cortesi and Couch, {Fergus J.} and Esther Darder and {de la Hoya}, Miguel and Michael Dean and Irmgard Debatin and {Del Valle}, Jesus and Janssen, {Linda Am} and {Gomez Garcia}, Encarna and {KConFab Investigators} and Spurdle, {Amanda B.}",
note = "Funding Information: kConFab and kConFab Clinical Follow Up Study: National Breast Cancer Foundation (Australia), National Health and Medical Research Council (NHMRC), Queensland Cancer Fund, Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, Cancer Foundation of Western Australia, and Cancer Australia. BCAC and iCOGS: Cancer Research UK (grant numbers C1287/A16563, C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the European Unions Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), the European Communitys Seventh Framework Programme under grant agreement no. 223175 (HEALTHF2–2009-223175) (COGS), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065-01 (DRIVE), and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), and the Canadian Institutes of Health Research CIHR) for the CIHR Team in Familial Risks of Breast Cancer (grant PSR-SIIRI-701). QIMR Berghofer Medical Research Institute: MT Parsons is supported by a grant from Newcastle University, UK E Tudini was supported by a grant from the National Health and Medical Research Council (NHMRC, ID1104808). Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",
year = "2019",
month = sep,
doi = "10.1002/humu.23818",
language = "English",
volume = "40",
pages = "1557--1578",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley",
number = "9",
}