The ICR639 CPG NGS validation series: A resource to assess analytical sensitivity of cancer predisposition gene testing

Wellcome Open Research

article

Shazia Mahamdallie¹  Elise Ruark¹  Esty Holt¹  Emma Poyastro-Pearson¹  Anthony Renwick¹  Ann Strydom¹  Sheila Seal¹  Nazneen Rahman¹ 

[1] Division of Genetics & Epidemiology, The Institute of Cancer Research;TGLclinical, The Institute of Cancer Research;Cancer Genetics Unit, Royal Marsden NHS Foundation Trust

关键词: next generation sequencing;    cancer predisposition gene;    BRCA1 and BRCA2;    analytical sensitivity;    genetic testing;    validation;    variant benchmarking;   

DOI  :  10.12688/wellcomeopenres.14594.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

The analytical sensitivity of a next generation sequencing (NGS) test reflects the ability of the test to detect real sequence variation. The evaluation of analytical sensitivity relies on the availability of gold-standard, validated, benchmarking datasets. For NGS analysis the availability of suitable datasets has been limited. Most laboratories undertake small scale evaluations using in-house data, and/or rely onin silico generated datasets to evaluate the performance of NGS variant detection pipelines. Cancer predisposition genes (CPGs), such asBRCA1 andBRCA2, are amongst the most widely tested genes in clinical practice today. Hundreds of providers across the world are now offering CPG testing using NGS methods. Validating and comparing the analytical sensitivity of CPG tests has proved difficult, due to the absence of comprehensive, orthogonally validated, benchmarking datasets of CPG pathogenic variants. To address this we present the ICR639 CPG NGS validation series. This dataset comprises data from 639 individuals. Each individual has sequencing data generated using the TruSight Cancer Panel (TSCP), a targeted NGS assay for the analysis of CPGs, together with orthogonally generated data showing the presence of at least one CPG pathogenic variant per individual. The set consists of 645 pathogenic variants in total. There is strong representation of the most challenging types of variants to detect, with 339 indels, including 16 complex indels and 24 with length greater than five base pairs and 74 exon copy number variations (CNVs) including 23 single exon CNVs. The series includes pathogenic variants in 31 CPGs, including 502 pathogenic variants inBRCA1 orBRCA2, making this an important comprehensive validation dataset for providers ofBRCA1 andBRCA2 NGS testing. We have deposited the TSCP FASTQ files of the ICR639 series in the European Genome-phenome Archive (EGA) under accession numberEGAD00001004134.

【 授权许可】

CC BY