Discussion
Started 9 March 2021
  • Henan Cancer Hospital

How to make a balance between the population frequency and the functional consequences of a mutation ?

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.

Most recent answer

Jun Li
Henan Cancer Hospital
Hi Martin Klvana , I do agree with u ~

All replies (4)

The data from population frequency (1.5%) and functional consequences (3/10000) do not contradict but complement each other. These numbers convey an important message: the mutation on its own is not the cause of the disease, and other factors come into play, which is quite common.
Jun Li
Henan Cancer Hospital
Hi Martin, thanks doe youe response~ I TOTALLY agree with you, however, my colleague assume that the population frequency could only be one piece of supporting evidence as benign; on the other hand, since the variants abolish the protein function, this is a pathogenic evidence. According to the ACMG guideline, sometime, if you can not find further evidence, then this variant has to be classified as VUS. Maybe it's a little bit abrup, but may I know how the western researchers, or clinician use the ACMG guideline for variant classification? In this guideline, they set the population frequency of 5% as a BA1 evidence, which I assume is too high.
Jun Li , this is not my field, but why not combining the two values into one, as a ratio: 0.00003 / 0.015 = 0.02, i.e., 1 in 50 carriers of the mutation develops the disease. That the mutation is rare is irrelevant: from the perspective of the carrier, 2% probability of developing the disease is not negligible. Of course, the individual probabilities might span a wide range around the average, and can probably be altered: So the key thing would be to find out what other factors come into play, and if any of them can be modulated on the level of an individual carrier. What do you think?
Jun Li
Henan Cancer Hospital
Hi Martin Klvana , I do agree with u ~

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