8. Example 3 Uncertain Significance PTEN Stop GainΒΆ

For the third example return to the VSClinical tab to look at the next variant, number 5. First look at the Clinical tab and notice that the PTEN variant is a stop gain and then move to the Population tab to analyze the population counts. It is shown again in this example that this variant is novel, so it captures the first layer of moderate evidence PM2. Next, move on to the Gene Impact tab.

Here investigation can further analyze the stop gain in the PTEN gene. The PVS1 criteria is presented for null variants in a gene where LOF is a known mechanism of disease (and note that PVS1 is the very strong evidence toward pathogenic classification). However, VSClinical provides critical insight into the fact that this variant is not only in the last exon of this gene, but also there are no records of other pathogenic stop gain variants downstream of this one. So, when following the recommendations for no to PVS1, the final classification is uncertain significance. It is important to note that even when faced with a potentially concerning stop gain, VSClinical is a solution to not only deep dive into the variant but also properly label this uncertain classification with the only criteria being PM2. It is possible in the future, with new evidence available, this classification could change, and the re-evaluation would be simple to process.

PVS1 reason for no

Figure 8-1: Analyzing the PVS1 reason for no criteria.

For the last example, we will look at the representation of an in-frame insertion.