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. 2024 Nov 7;111(11):2411-2426.
doi: 10.1016/j.ajhg.2024.08.022. Epub 2024 Sep 23.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants

Marcy E Richardson  1 , Megan Holdren  2 , Terra Brannan  3 , Miguel de la Hoya  4 , Amanda B Spurdle  5 , Sean V Tavtigian  6 , Colin C Young  3 , Lauren Zec  7 , Susan Hiraki  8 , Michael J Anderson  9 , Logan C Walker  10 , Shannon McNulty  11 , Clare Turnbull  12 , Marc Tischkowitz  13 , Katherine Schon  13 , Thomas Slavin  14 , William D Foulkes  15 , Melissa Cline  16 , Alvaro N Monteiro  17 , Tina Pesaran  3 , Fergus J Couch  18
Affiliations

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants

Marcy E Richardson et al. Am J Hum Genet. .

Abstract

The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

Keywords: ACMG; ATM; ClinGen; Variant Curation Expert Panel; ataxia telangiectasia; breast cancer; classification; rules specifications; variant interpretation.

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Conflict of interest statement

Declaration of interests M.J.A. was a paid employee of Invitae. M.E.R., T.B., T.P., and C.C.Y. were paid employees of Ambry Genetics. L.Z. was a paid employee of Natera. S.H. was a paid employee of GeneDx.

Figures

Figure 1
Figure 1
ATM exon numbering and reading frame ATM is depicted exon by exon. The number of amino acids encoded by each exon is depicted within the boxes in black text. The two major functional domains are outlined in blue (N-solenoid, comprised of sub-domains HEAT repeat and TAN domain) and green outline (FATKIN domain comprised of the FAT and FAT-C sub-domains). Each exon is shaped to indicate the number of overhanging nucleotides at either end, which will assist in determining any reading-frame changes from gross deletions or duplications of whole single- or multi-exons. A vertical line indicates a blunt start or end with no overhanging nucleotides. An upper overhang on either side represents a two-nucleotide overhang; a lower overhang represents a single-nucleotide overhang on that side. To use this diagram, a line drawn at the start and end of a deletion or duplication will be either parallel (in-frame event) or non-parallel (frameshift) as in the examples.
Figure 2
Figure 2
ATM pilot variant categorization Thirty-three pilot variants are displayed as community classification in ClinVar (top) where VUS/LP/P conflicting interpretation variants and VUS/LB/B conflicting interpretation variants are binned along with consensus VUS as “ClinVar VUS/Conflict.” Interpretation with the HBOP rules specifications for ATM are on the bottom. Granular detail of the type of conflict and the type of variant are presented in Table S4.
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References

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