Updated recommendation for the benign stand-alone ACMG/AMP criterion.

Hum Mutat
Authors
Keywords
Abstract

The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group set out to refine the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG/AMP) variant pathogenicity recommendations for stand-alone rule BA1 (a variant with minor allele frequency [MAF] > 0.05 is benign), by clarifying how it should be used and specifying a set of variants that should be exempted from this rule. We cross-referenced ClinVar and Exome Aggregation Consortium data to identify variants for which there was a plausible argument for pathogenicity and the variant exists in one or more population data sets at MAF > 0.05. We identified nine such variants that were present in these data sets that may not be benign. The ACMG/AMP criteria were applied to these variants that resulted in four pathogenic and five variants of uncertain significance. We have refined benign rule BA1 by clarifying terms used to describe its use, which databases we recommend using, and assumptions made about this rule. We also recognized an initial list of nine variants for which there was some evidence of pathogenicity even though the MAF was high for these variants. We specify processes whereby individuals can petition ClinGen for amendments to our variant-specific assertions and the criteria experts should use when setting a numerically lower threshold for BA1 for specific genes.

Year of Publication
2018
Journal
Hum Mutat
Volume
39
Issue
11
Pages
1525-1530
Date Published
2018 Nov
ISSN
1098-1004
DOI
10.1002/humu.23642
PubMed ID
30311383
PubMed Central ID
PMC6188666
Links
Grant list
U41 HG006834 / HG / NHGRI NIH HHS / United States
ZIA HG200328-13 / ImNIH / Intramural NIH HHS / United States
ZIA HG200359-09 / ImNIH / Intramural NIH HHS / United States
U41HG009650 / CA / NCI NIH HHS / United States