5. ACMG GuidelinesΒΆ

After running the ACMG Sample Classifier algorithm, opening the ACMG Guidelines is as easy as opening a new tab and selecting VS Clinical, and then selecting ACMG Guidelines from the drop-down menu.

add vsclinical tab

Figure 5-1: Adding the VSClinical tab.

ACMG guidelines tab

Figure 5-2: Selecting the ACMG Guidelines tab.

This will open up a dialog that will ask the user to specify which assessment catalog to use (or create a new catalog), which variant record set to us as a list of possible variants to interpret, and if desired, with record sets to use for Primary Findings and Secondary Findings.

ACMG options dialog

Figure 5-3: Opening the VSClinical ACMG Options dialog.

For this tutorial, we will use the Assessment Catalog we created earlier by finding it in the drop-down menu and creating a new record set for Variants to analyze. Selecting the Add button in the Input Variants to Interpret dialog box will bring up a Create Variant Set dialog where the Name, initials for the column title, and color can be customized. We will keep the default values for this example. This will also be repeated for the Primary Findings variant set and Secondary Findings variant set.

create variant set

Figure 5-4: Create variant set dialog.

Now the VSClinical ACMG Options dialog is complete and then we can select OK.

adjust vsclinicla acmg options

Figure 5-5: Adjust variant sets in VSClinical ACMG Options dialog.

At this point the ACMG Guidelines tab is ready to start an evaluation. This requires selecting variants to evaluate by adding them to the To Evaluate variant set. Three are two ways to do this selection, from the Variants to Evaluate section in the current ACMG Guidelines tab or back in the Variants table. We will proceed by going to the Variants tab and selecting the top five variants and adding them to the EV variant set.

add variant set

Figure 5-6: Add variants to variant set.

Selecting variants now updates the variant count in the ACMG Guidelines tab based on the To Evaluate variants just selected in the variants tab.

ACMG guidelines screen

Figure 5-7: ACMG Guidelines opening screen.

The evaluation is started by selecting the blue Start New Evaluation button, and then selecting Continue after the algorithm checks whether the selected variants have been previously classifed.

create new ACMG evaluation

Figure 5-8: Creating a new ACMG evaluation.

The ACMG Guidelines tab will open up on the main Classification page in the center and the Variant information in the sidebar.

acmg guidelines evaluation screen

Figure 5-9: The ACMG Guidelines evaluation screen.

The collapsable right sidebar can be used to switch the evaluation to other variants as well as see summary information about the current variant. Each variant is represented with a box with the variant names available on hover. The boxes are filled in when the variant is evaluated and saved. The color of the outline and the fill-in color correlate to the ACMG classification of each variant. The color scheme is as follows:

ACMG guidelines color scale

Figure 5-10: ACMG Guidelines pathogenicity color scheme.

Each variant is automatically evaluated by the ACMG recommendation engine, with many of the individual criteria receiving recommendations on whether it should be answered Yes or No as well as detailed reasons for these recommendations.

In the Evidence Summary section, criteria that are recommended will be listed under Recommended to Score Pathogenic and Recommended to Score Benign. The name of the recommended criteria are in colored bubbles with arrow links to navigate to the tab and section containing the criteria question and supporting evidence.

Criteria questions are organized in the following tabs: Population, Gene Impact, Studies, and Clinical. In the following pages of this tutorial, we will go through a number of examples that will take us through these tabs. As we answer criteria questions, note how the right bar ACMG Scoring section will update with the currently scored criteria and resulting ACMG Classification.

The following examples are taken from the evaluation created with our specific filtering and sorting efforts. The first example is an interesting frameshift in the MSH6 gene that at first looks to be pathogenic, but ends up being discovered to be benign.