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The ACMG standards and guidelines were developed to help clinical laboratory geneticists provide a structured resource for clinical laboratories. Although there are many well-characterized recurrent copy number variations (CNVs) that are available in numerous public databases (DGV, ClinGen, OMIM, etc.), there are as many unique CNVs that require further investigation in determining their potential clinical significance. To promote consistency and reduce confusion among clinical labs in determining the clinical significance of CNVs, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) published Technical Standards for the Interpretation and Reporting of Constitutional Copy-Number Variants (Riggs et al., 2019). These standards have been widely implemented by clinical labs around the world. However, the tools to calculate the ACMG scores for classification have still not been widely integrated with CNV analysis software and analysts are left to use web-based or separate in-house calculators to score the variant.

The most recent version of NxClinical, the leading CNV analysis software for clinical cytogenetics and molecular labs, now includes an integrated ACMG guidelines scoreboard feature. This feature automatically calculates the score for many of the evidence categories described by the ACMG standards.

ACMG scoreboard in NxClinical

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The ACMG guidelines scores for each section are displayed at the bottom of the variant details tab. The scores for each section are added together resulting in the final overall score and subsequent classification of the event.

The scoreboard is designed with the flexibility to manually add additional evidence score(s) and modify the scores for each evidence category using professional expertise to arrive at a final interpretation. Additionally, there is a notes section for each evidence category where the analyst can input text with regards to why that score was entered. Overall, the feature provides a formal reasoning structure that standardizes CNV event classification and ultimately helps reduce errors in classifying events by eliminating the need to use external tools.

expanded ACMG guidelines

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Partial view of the expanded ACMG guidelines sections where the scores can be manually modified and notes can be included by geneticists.

In addition to using the scoreboard as a stand-alone guideline, this new feature can be coupled with NxClinical's popular automated variant pre-classification decision tree to pre-classify events. This allows analysts to quickly sort through the events on the table and prioritize for review.

ACMG 2019 pre-classified events table

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Events table sorted by the classification column for pre-classified events using a decision tree based on the ACMG scoring guidelines. The pre-classification comments column provides additional information on the automated decision tree and the ACMG score.

In the end, the use of the ACMG guidelines scoreboard in the decision tree results in reduced time spent on interpreting each variant and more efficient overall sample analysis. To read more about this specific process view our poster from ASHG 2021 titled Automated Classification of Copy Number Variants Based on 2019 ACMG Standards.

For existing customers who are interested in requesting this NxClinical feature upgrade please contact us. If you are not a current customer and would like to request a NxClinical demo to see the ACMG scoreboard in action please submit this form.

References:

Riggs, E.R., Andersen, E.F., Cherry, A.M. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22,245–257 (2020). https://doi.org/10.1038/s41436-019-0686-8