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[Preprint]. 2024 May 29:2024.05.28.24307502.
doi: 10.1101/2024.05.28.24307502.

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

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

Marcy E Richardson et al. medRxiv. .

Update in

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 ACMG/AMP guidelines for the ataxia telangiectasia mutated (ATM) gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for ATM were modified from the American College of Medical Genetics and Association for Molecular Pathology (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 reevaluation 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 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.

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Conflict of interest statement

Declaration of Interests MA and SN were a paid employee of Invitae. MER, TB, TP, CCY, and were paid employees of Ambry Genetics. LZ was a paid employee of Natera. SH was a paid employee of GeneDx.

Figures

Figure 1.
Figure 1.
ATM Exon Numbering and Reading Frame. The ATM gene is depicted exon-by-exon. The amino acid size of each exon is depicted within the boxes in black text. The two major functional domains are outlined in red (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.
PVS1 Decision Tree for ATM. PVS1 eligible variant types are split into five categories: initiation codon variants, nonsense and frameshift variants, ≥1 exon deletions, ≥1 exon duplications and last NT/canonical splice variants. Considerations related to NMD, N and C terminal boundaries, domain involvement, tandemness, and splice prediction/observation inform the weight that can be afforded to the PVS1 criterion. Small in-frame events were predicted with PROVEAN and scores are provided. Nucleotides in red-underline have splice effects reported in the literature.
Figure 2.
Figure 2.
PVS1 Decision Tree for ATM. PVS1 eligible variant types are split into five categories: initiation codon variants, nonsense and frameshift variants, ≥1 exon deletions, ≥1 exon duplications and last NT/canonical splice variants. Considerations related to NMD, N and C terminal boundaries, domain involvement, tandemness, and splice prediction/observation inform the weight that can be afforded to the PVS1 criterion. Small in-frame events were predicted with PROVEAN and scores are provided. Nucleotides in red-underline have splice effects reported in the literature.
Figure 2.
Figure 2.
PVS1 Decision Tree for ATM. PVS1 eligible variant types are split into five categories: initiation codon variants, nonsense and frameshift variants, ≥1 exon deletions, ≥1 exon duplications and last NT/canonical splice variants. Considerations related to NMD, N and C terminal boundaries, domain involvement, tandemness, and splice prediction/observation inform the weight that can be afforded to the PVS1 criterion. Small in-frame events were predicted with PROVEAN and scores are provided. Nucleotides in red-underline have splice effects reported in the literature.
Figure 3.
Figure 3.
ATM Pilot Variant Categorization. 33 pilot variants are displayed as community classification in ClinVar (left) 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 right. Granular detail of the type of conflict and the type of variant are presented in the table. PTC: Premature Termination Codon; CV: ClinVar
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