Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions

The clinical classification of variants may change with new information, however, there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant dat...

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Veröffentlicht in:Human mutation Jg. 43; H. 12; S. 2054 - 2062
Hauptverfasser: Davidson, Aimee L., Kondrashova, Olga, Leonard, Conrad, Wood, Scott, Tudini, Emma, Hollway, Georgina E., Pearson, John V., Newell, Felicity, Spurdle, Amanda B., Waddell, Nicola
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States John Wiley & Sons, Inc 01.12.2022
Schlagworte:
Classification
ClinVar
Genetic Predisposition to Disease
Genetic Testing
Genetic Variation
Genomics
hereditary cancer genes
Humans
Neoplasms - diagnosis
Neoplasms - genetics
Pathogenicity
reanalysis
Software
United States
variant classification
United States
variant classification
genomics
hereditary cancer genes
reanalysis
ClinVar
ISSN:1059-7794, 1098-1004, 1098-1004
Online-Zugang:Volltext
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Zusammenfassung:The clinical classification of variants may change with new information, however, there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant data from ClinVar between January 2015 and July 2021. The ClinVar‐assigned “aggregate” classification of variants in 121 hereditary cancer genes was harmonized across releases to align to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology terms. Aggregate classification categories were grouped as: benign/likely benign (B/LB); likely pathogenic/pathogenic (LP/P); variant of uncertain significance (VUS); conflicting interpretations of pathogenicity (Conflicting); or Other. We profiled changes in aggregate variant classification between consecutive semi‐annual ClinVar releases. The proportion of variants that changed aggregate classification between semi‐annual ClinVar releases ranged from 0.6% to 6.4%. The most frequent changes were “VUS to conflicting,” “other to LP/P,” and “B/LB to Conflicting.” A limited number of variants changed aggregate classification from “LP/P to B/LB,” or vice versa. Our analysis indicates need for regular reassessment of clinical variant interpretations. The parser developed for this project will facilitate extraction of relevant interpretation data from ClinVar. Modelling changes in classification of variants in cancer genes over time
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ISSN:1059-7794
1098-1004
1098-1004
DOI:10.1002/humu.24468