Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretationReportar como inadecuado

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Genome Medicine

, 9:13

First Online: 06 February 2017Received: 06 September 2016Accepted: 13 January 2017DOI: 10.1186-s13073-017-0403-7

Cite this article as: Kobayashi, Y., Yang, S., Nykamp, K. et al. Genome Med 2017 9: 13. doi:10.1186-s13073-017-0403-7


BackgroundThe frequency of a variant in the general population is a key criterion used in the clinical interpretation of sequence variants. With certain exceptions, such as founder mutations, the rarity of a variant is a prerequisite for pathogenicity. However, defining the threshold at which a variant should be considered -too common- is challenging and therefore diagnostic laboratories have typically set conservative allele frequency thresholds.

MethodsRecent publications of large population sequencing data, such as the Exome Aggregation Consortium ExAC database, provide an opportunity to characterize with accuracy and precision the frequency distributions of very rare disease-causing alleles. Allele frequencies of pathogenic variants in ClinVar, as well as variants expected to be pathogenic through the nonsense-mediated decay NMD pathway, were analyzed to study the burden of pathogenic variants in 79 genes of clinical importance.

ResultsOf 1364 BRCA1 and BRCA2 variants that are well characterized as pathogenic or that are expected to lead to NMD, 1350 variants had an allele frequency of less than 0.0025%. The remaining 14 variants were previously published founder mutations. Importantly, we observed no difference in the distributions of pathogenic variants expected to be lead to NMD compared to those that are not. Therefore, we expanded the analysis to examine the distributions of NMD expected variants in 77 additional genes. These 77 genes were selected to represent a broad set of clinical areas, modes of inheritance, and penetrance. Among these variants, most 97.3% had an allele frequency of less than 0.01%. Furthermore, pathogenic variants with allele frequencies greater than 0.01% were well characterized in publications and included many founder mutations.

ConclusionsThe observations made in this study suggest that, with certain caveats, a very low allele frequency threshold can be adopted to more accurately interpret sequence variants.

KeywordsAllele-frequency threshold Variant interpretation ExAC ACMG ISV guidelines AbbreviationsACMGAmerican College of Medical Genetics and Genomics

AMPAssociation for Molecular Pathology

ExACExome Aggregation Consortium

EVSExome Variant Server

HBOCHereditary breast and ovarian cancer

HGMDHuman Genome Mutation Database

MAFMinor allele frequency

NMDNonsense-mediated decay

PCDPrimary ciliary dyskinesia

pLIProbability of being loss-of-function intolerant

RVISResidual variation intolerance scores

TCGAThe Cancer Genome Atlas

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-017-0403-7 contains supplementary material, which is available to authorized users.

Autor: Yuya Kobayashi - Shan Yang - Keith Nykamp - John Garcia - Stephen E. Lincoln - Scott E. Topper


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