Toward automation of germline variant curation in clinical cancer genetics

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Vignesh RavichandranJoseph Vijai

Abstract

Cancer care professionals are confronted with interpreting results from multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches and aggregation of multiple lines of evidence from diverse resources. The clinical genetics community needs a fast algorithm that automates American College of Medical Genetics and Genomics (ACMG) based variant classification and provides uniform results. Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein, and disease specific information from public sources. We compared expertly curated variant data from clinical laboratories to assess performance. PathoMAN achieved a high overall concordance of 94.4% for pathogenic and 81.1% for benign variants. We observed negligible discordance (0.3% pathogenic, 0% benign) when contrasted against expert curated variants. Some loss of resolution (5.3% pathogenic, 18.9% benign) and gain of resolution (1.6% pathogenic, 3.8% benign) were also observed. Automation of variant curation enables unbiased, fast, efficient delivery of results ...Continue Reading

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Dec 4, 2019·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Maria I CarloKenneth Offit
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Dec 16, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Erin ZampaglioneKinga M Bujakowska

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Methods Mentioned

BETA
exome sequencing
genotyping

Software Mentioned

ClinVar
MyVISION
ClinGen
ExAC
ENIGMA
noTCGA
gnomAD
CAVA
ANNOVAR
InterVar

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