8. Example 1 SNV RAF1 S257LΒΆ

Since the RAF1 variant was added as a germline variant, the variant page is formatted to utilize the ACMG Guidelines which were discussed in a previous ACMG tutorial found here. But to review the classification that was reached here, scroll down to the ACMG Criteria Recommendations section and review the criteria that were selected to reach the classification of Pathogenic.

acmg criteria recommendations

Figure 8-1: The ACMG Criteria Recommendations for Example 1.

The first criteria selected, PM2 was added since the variant is novel in gnomAD and 1000 Genomes population catalogs. Next, PM1 was selected since nearby variants have shown to be pathogenic as well. The third criteria, PP2 was selected since this RAF1 variant is a missense variant with a high Z-Score and therefore has a higher likelihood to be pathogenic by its very nature. The fourth criteria, PP3 relates that both GERP++ and PhyloP predicted damaging and conserved across different species and the fifth criteria, PM5 confirms pathogenic by showing that this variant has been classified as pathogenic in ClinVar. This was a straight-forward pathogenic variant but note that the scored criteria and the pathogenic classification are reflected in the variant sidebar on the right.

After confirming the classification of this variant, scroll down in the main page to the next section, Report Secondary Germline, to create the interpretation that will be used in the final report.

This section shows the variant classification and allows the user to specify the related disorder and inheritance model. The interpretation was created by adding explanations from the different scoring criteria in the Scored Criteria section of the variant and added to the text box on the left by selecting the button, Add to Interpretation. This section represents all of the information for this variant that will be carried to the final report.

acmg report interpretation

Figure 8-2: Report Secondary Germline interpretation section.

As mentioned previously, the user can scroll down from this section to re-analyze any of the scored criteria in the ACMG analysis of this germline variant. Next, we will look at the other Small Variant, the BRAF variant by selecting the 1 card at the top of the sidebar on this page.

amp guidelines variant selection

Figure 8-3: The AMP Guidelines Variants tab variant selection.