6. Example 1 Benign MSH6 p.K1358Dfs*2

The first example will be the first variant card which is looking at the frameshift variant in the MSH6 gene. The red bubbles across the tab titles show that there is 1 critical criterion to explore in the Population tab and one in the Gene Impact tab. First, navigate to the Gene Impact tab by selecting it.

ACMG guidelines classification

Figure 6-1: The ACMG Guidelines Classification tab.

Select and expand open the Tolerant Loss of Function Mutations section within the Gene Impact tab. Each section features one or more ACMG criteria questions along with supporting evidence formated in specialized cards. This section contains the question for PVS1, the strongest pathogenic criteria in the ACMG guidelines: Null variant in a gene where LOF is a known mechanism of disease.

By clicking the ‘Show Details’ expander, we see in the provided details that although there are other pathogenic LOF variants in MSH6, the variant in question is in the very last exon of the gene, and there are no other pathogenic variants downstream. So in this case, we follow the highlighted recommendation and answer No to the PVS1 criteria.

ACMG guidelines gene impact

Figure 6-2: The ACMG Guidelines Gene Impact tab.

PVS1 scoring criteria

Figure 6-3: Analyzing the PVS1 scoring criteria.

Next we will review the frequency of this variant by selecting the Population tab and expanding the gnomAD Exomes Frequency and 1000 Genomes Frequency sections.

Despite being a gene with known pathogenic LOF variants, the specific variant is present at a frequency greater than 3% in East Asian populations in the gnomAD catalog. It is also worth mentioning that as of the 2015 publication on the original ACMG guidelines default frequency threshold for BA1 is 5% but Golden Helix implements the more clinically accepted 1% threshold. These details are described not only in Tolerated Frequency section at the top of this tab but also the integrated documentation about each criteria question (which can be viewed by selecting See further discussions on BA1 in the Details section for BA1).

ACMG guidelines population

Figure 6-4: The ACMG Guidelines Population tab.

So, to sum this variant up, there is an initial concern for pathogenic criteria, but frequency alone is enough to classify this variant as benign for BA1 standalone evidence. This is the first example among many on how VSClinical simplifies the interpretation of all ACMG based evidence. Next, we will look at a straight-forward pathogenic variant.