期刊
HUMAN MUTATION
卷 40, 期 9, 页码 1557-1578出版社
WILEY
DOI: 10.1002/humu.23818
关键词
BRCA1; BRCA2; classification; clinical; multifactorial; quantitative; uncertain significance; variant
资金
- Wellcome Trust [203477/Z/16/Z] Funding Source: Wellcome Trust
- AstraZeneca Funding Source: Medline
- Cancer Council NSW Funding Source: Medline
- Cancer Council South Australia Funding Source: Medline
- Cancer Council Tasmania Funding Source: Medline
- Cancer Council Victoria Funding Source: Medline
- Cancer Foundation of Western Australia Funding Source: Medline
- Cancer Research UK [C5047/A15007, C1281/A12014, C5047/A10692, C1287/A10118, C1287/A10710, C1287/A16563, C8197/A16565, C5047/A8384, C12292/A11174] Funding Source: Medline
- CIHR [PSR-SIIRI-701] Funding Source: Medline
- Deutsche Krebshilfe [(#110837, #70111850] Funding Source: Medline
- Dutch Cancer Society KWF [KWF/Pink Ribbon-11704, UL2012-5649] Funding Source: Medline
- EU H2020 [634935] Funding Source: Medline
- Generalitat de Catalunya [2017SGR1282, URDCat, 2017SGR496, PERIS_MedPerCan] Funding Source: Medline
- Instituto de Salud Carlos III [FIS PI16/01218, CIBERONC, FIS PI13/01711, FIS PI15/00355, PI16/00563] Funding Source: Medline
- Italian Association of Cancer Research [15547] Funding Source: Medline
- National Council of Technological and Scientific Development (CNPq) Funding Source: Medline
- National Health and Medical Research Council [ID1061778, ID1104808] Funding Source: Medline
- National Institute for Health Research [Manchester Biomedical Research centre (IS-BRC-1215] Funding Source: Medline
- National Institute of Health (USA) [CA192393, 1U19 CA148112, 1U19 CA148065-01, P50 CA1162091, 1U19 CA148537, CA116167, CA128978] Funding Source: Medline
- NCI NIH HHS [R01 CA121245, R01 CA192393, U01 CA116167] Funding Source: Medline
- Netherlands Organization for Scientific Research (NWO) [Grant 017.008.022] Funding Source: Medline
- Royal Society of New Zealand Funding Source: Medline
- Seventh Framework Programme [634935, 633784, 223175] Funding Source: Medline
- Wellcome Trust [203477/Z/16/Z] Funding Source: Medline
- Queensland Cancer Fund Funding Source: Medline
- Ohio State University Comprehensive Cancer Center Funding Source: Medline
- Fondazione Pisa [Grant Clinical characterization of BRCA 1/2 Mis] Funding Source: Medline
- Breast Cancer Foundation of New Zealand Funding Source: Medline
- Newcastle University Funding Source: Medline
- Department of Defence, USA [W81XWH-10-1-0341] Funding Source: Medline
- Centro de Investigación Biomédica en Red de Enferemdades Raras [ACCI 2016: ER17P1AC7112/2018] Funding Source: Medline
- Helsinki University Hospital Research fund Funding Source: Medline
- French National Institute of Cancer Funding Source: Medline
- Barretos Cancer Hospital [FINEP - CT-INFRA (02/2010)] Funding Source: Medline
- National Breast Cancer Foundation Funding Source: Medline
- Breast Cancer Research Foundation Funding Source: Medline
- Government of Galicia [Consolidation and structuring program: IN607B] Funding Source: Medline
- Leiden University Medical Centre [Grant 30.925] Funding Source: Medline
- Fundación Mutua Madrileña Funding Source: Medline
- Carlos III National Health Funding Source: Medline
- Scientific Foundation Asociación Española Contra el Cáncer Funding Source: Medline
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.
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