Recently, I had some discussion with another colleague about the classification of variants detected in our routine clinical care. Here's an example, the gene A is involved in homologous recombination repair, truncating mutation in A increased the risk of developing breast/ovarian cancer, or other cancers.We detected a missense variant in gene A, but the population frequency of this variant, let's say 1.5%, is higher than the occurance of this risease (3/10000)； meanwhile, there are other evidence, functional study or in silico prediction, show that the change leads to HR defect.
In my personal perspective, I woud give a higher weight to the population frequency. Although functional study or in silico prediction shows this variant leads to HRD, the carriers didn't show increased cancer risk; therefore, I would consider this variant as benign OR likely benign.
My colleague, however, has a different opinion that she would like to classify this variant as VUS (variant of unknown significance), since the evidence from population frequency and functional consequences are contradict to each other.
May I know your opinion ? I would appreciate your sharing.
