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A commentary on actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes

Journal of Human Genetics volume 67, pages 617–619 (2022)Cite this article

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We read the article by Chetruengchai and Shotelersuk [1] with interest as it provided an estimate of ACMG v3.0 secondary findings [2] in an unselected Thai population. In a cohort of 1559 unrelated individuals a finding of 22 pathogenic (P)/likely pathogenic (LP) variants was asserted in 15 genes associated with 13 diseases in 85 individuals for a secondary variant rate of 5.5%. We question the validity of this claim, based on our understanding of current variant classification standards [3]. The 22 variants detailed in Chetruengchai and Shotelersuk as secondary findings were classified as P or LP by VarSome [4] and at least one submitter in ClinVar [5], without further assessment by the authors. It is widely recognized that a substantial number of individual classifications in ClinVar are incorrect and that they must be reviewed to confirm evidence is sufficient to support the final classification and applicable to the phenotype in question. While tools such as VarSome are useful in providing evidence that can inform the ACMG/AMP/ClinGen criteria, VarSome is not a replacement for expert opinion and does not strictly adhere to ACMG/AMP/ClinGen guidance. Final classification as to whether a variant is P/LP should be determined after a review of all available data using the relevant ACMG/AMP/ClinGen standards [3, 6]. In addition to using tools such as VarSome and ClinVar, mining primary data that support or refute criteria relevant to ACMG/AMP pathogenicity classification is critical to providing the best possible variant classification, based on the current state of knowledge. The primary literature and variant databases can inform criteria including PS2/PS4/PP4/BS2/BP2/BP5 (case information), PP1/BS4 (segregation) and PS3/BS3 (functional data). The individual classifying the variant must confirm that sufficient data have been identified and are correctly applied to the ACMG criteria.

It is also important to use the current ACMG/AMP/ClinGen guidance on application of evidence and the final combining rules when classifying variants. Chetruengchai and Shotelersuk assigned PVS1 and PP3 in combination to several variants, however, PVS1 assumes loss of function and thus no additional weight should be awarded for the prediction of such (PP3, bioinformatic prediction) [7]. Several variants that are relatively common in gnomAD (popmax maf >0.1%) were assigned criterion PM2, which gives weight for rarity in the population. For variants in KCNQ1, SCN5A, and RYR1 it appears that PM2 was assigned based on autosomal recessive inheritance (allowing a higher minor allele frequency) even though the associated disorders on the ACMG SF v3.0 gene list demonstrate autosomal dominant inheritance. For genes that are associated with multiple phenotypes the variant scientist must consider the phenotype under consideration when assigning criteria [2, 8]. As well, variants were not strictly classified using either the combining rules as presented in Richards et al. or the Bayes combining metric [3, 9]. Variant classifiers that conform to current ACMG/AMP/ClinGen standards will be instrumental in allowing larger data sets to be analyzed although providers will still hold responsibility for final classifications.

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Authors and Affiliations

  1. Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Jennifer J. Johnston, Seeley Yoo & Leslie G. Biesecker

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  1. Jennifer J. Johnston
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Conceptualization: JJJ, LGB; Data curation: JJJ, SY; Writing-original draft: SY; Writing-review & editing: JJJ, LGB.

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Correspondence to Jennifer J. Johnston.

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LGB is an uncompensated advisor of Illumina.

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Johnston, J.J., Yoo, S. & Biesecker, L.G. A commentary on actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes. J Hum Genet 67, 617–619 (2022). https://doi.org/10.1038/s10038-022-01037-w

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