Variant of Unknown Significance
As the number of genes available for sequencing is increasing, we are finding more and more genetic variants of unknown significance, which are hard to interpret. These pose particular challenges in communicating the uncertainties to patients and their families.
The term ‘variant of unknown significance’ is associated with the type of gene change where we don’t know if it may cause cancer or if it is just a natural variation in the genetic code. If you think of a gene as an instruction for the cell that is read in 3-letter words, then take a sentence THE CAT ATE THE RAT. This makes complete sense. But if you lose a letter e.g. The “T” in CAT then everything after that gets shifted up one place and you get this:
THE CAA TET HER AR – this makes no sense and is likely to be a true mutation (the same could happen by adding a letter as the gene is always read in 3 letter words).
If you have a PALB2 mutation of unknown significance, the sentence could look something like this:
THE CAT ATE THE BAT. It still makes sense, and could be right, or it could be wrong (did the cat eat the rat or the bat?). We don’t know, so we call it a Variant of Unknown Significance (VUS).
Various methods can be used to evaluate a variant’s ability to cause a disease, such as computer prediction programs or by looking how frequently it occurs in the general population (if it is very common, it is unlikely to be causing a disease). But such methods often lead to results which are inconsistent and hard to interpret (Moret et al, 2015). Further, the reporting of VUS may cause unnecessary anxiety and/or may not provide the sufficient information to patients.
According to Dr Marc Tischkowitz, if you have PALB2 mutation of unknown significance, you need to have a careful discussion with your genetics team about this. Sometimes other family members might be tested to see if the variant ‘tracks’ with the cancers, but usually this is only helpful if many family members can be tested which is often not possible. Finally, as we are learning about these variants all the time, it is important to keep in touch with your genetics team and ask them for an update every few years.
If you have a confirmed PALB2 mutation or/and others in your family have been found to have a PALB2 mutation, please contact us. Thank you.
Moret, C., Hurst, S.M. and Mauron, A. (2015) “Variants Of Unknown Significance And Their Impact On Autonomy”, The American Journal of Bioethics, vol. 15, issue 7, pp. 26-28 [Online]. Available at http://www.tandfonline.com/doi/full/10.1080/15265161.2015.1039727 (Accessed 7 April 2016).