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. 2022 Mar;24(3):736-743.
doi: 10.1016/j.gim.2021.11.012. Epub 2021 Nov 18.

The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort

Jennifer J Johnston  1 , Marie-Luise Brennan  2 , Bailey Radenbaugh  3 , Seeley J Yoo  3 , Sophia M Hernandez  3 ; NHGRI Reverse Phenotyping Core  3 ; Katie L Lewis  3 , Alexander E Katz  3 , Teri A Manolio  4 , Leslie G Biesecker  3
Affiliations

The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort

Jennifer J Johnston et al. Genet Med. 2022 Mar.

Abstract

Purpose: The American College of Medical Genetics and Genomics (ACMG) recommends the return of pathogenic and likely pathogenic (P/LP) secondary findings from exome and genome sequencing. The latest version (ACMG secondary finding [SF] v3.0) includes 14 additional genes. We interrogated the ClinSeq cohort for variants in these genes to determine the additional yield in unselected individuals.

Methods: Exome data from 1473 individuals (60% White, 34% African American or Black, 6% other) were analyzed. We restricted our analyses to coding variants; +1,+2,-1, and -2 splice site variants; and the pathogenic GAA variant, NM_000152.5:c.-32-13T>G. Variants were assessed with slightly modified ACMG/Association of Molecular Pathology guidelines.

Results: A total of 25 P/LP variants were identified. In total, 7 individuals had P/LP variants in genes recommended for return of heterozygous variants, namely HNF1A (1), PALB2 (3), TMEM127 (1), and TTN (2). In total, 4 individuals had a homozygous variant in a gene recommended for biallelic variant return, namely HFE, NM_000410.3(HFE):c.845G>A p.Cys282Tyr. A total of 17 P/LP variants were identified in the heterozygous state in genes recommended only for biallelic variant reporting and were not returned. The frequency of returnable P/LP variants did not significantly differ by race.

Conclusion: Using the ACMG SF v3.0, the returnable P/LP variant frequency increased in the ClinSeq cohort by 22%, from 3.4% (n = 50, ACMG SF v2.0) to 4.1% (n = 61, ACMG SF v3.0).

Keywords: ACMG SF v3.0; ClinSeq; Reverse phenotyping; Secondary findings; Variant classification.

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Conflict of interest statement

Conflict of Interest L.G.B. is an uncompensated advisor for Illumina. All other authors declare no conflicts of interest.

References

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