In this explainer episode, we’ve asked Helen Brittain, Clinical Lead for Rare Disease Diagnostics at Genomics England, to explain what a variant of uncertain significance is, in less than 10 minutes. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/What-is-a-variant-of-uncertain-significance.docx Naimah: What is a variant of uncertain significance? Today I’m joined by Helen Brittain, who’s the clinical lead for rare disease diagnostics at Genomics England, to find out more. So first of all, Helen, before we dive into the topic, I’d like to go one step further back and ask you to explain what is a gene? Helen: A gene is effectively a section of our DNA, which is our genetic code, and it contains an instruction, something important about how we grow, how we develop, how we function as a human. Humans in total have around 20,000 genes, which is our complete set of instructions, to tell us everything we need to know about ourselves. Naimah: So, what are gene variants then, and do they all have an effect? Helen: Variants are effectively differences within genes. So genes, like I said, are instructions, and they have a particular way that they’re spelled out and structured, so that the body can understand them and make sense of that instruction. A variant is where there’s something different about the way that that gene is spelled out or structured that could affect how it works, and basically a variant is a difference to what we expect to see. Naimah: And do all of these have an effect? Helen: So no, not all of them will have an effect. Some differences or variants within a gene may not affect the way it works at all, whereas others might alter that gene so significantly that it can’t do its job anymore, and could be very significant for that person’s health. Naimah: And how do we find these gene variants? Helen: Gene variants are exactly what we’re looking for when we’re trying to find a diagnosis for somebody. So, somebody with a rare condition is likely to have an underlying difference within their genes that would be the explanation for it. We’re finding these through doing genetic testing or genomic testing, so looking at an individual gene, a series of genes, or even across someone’s entire genetic code, through whole genome sequencing, and we find these variants through doing that testing. Naimah: And this might be a good opportunity to mention our other Genomics 101 episode on genetic testing, if you’d like to find out some more information on that as well. So, moving on with the next question, how is a variant’s significance determined? Helen: Variants, as we say, come from the genetic tests we undertake, and there are a team of people who look at and try to determine what effect that variant might have on that person. This is the majority of the time the work done within the laboratory teams, through the clinical scientists, who have expertise in understanding the impact of variants within a gene, and they work together with other clinical representatives, like the clinician looking after the patient, to understand that patient’s disease in as much detail as they can, to try to pull all of the information together and determine whether that variant is making a difference or not. They would look at a lot of different pieces of information to try to work out, could this be the reason behind that person’s genetic disorder? And that might be things like have we seen it before, can we predict the effect of that variant on the gene? And we have to understand how variants within that gene cause a condition to be able to match up against the variant that’s seen, as to whether that would make sense for that individual. So, it’s a lengthy process but an important one, to make sure that we’ve got the most accurate information about that variant, and the understanding about that in that person’s health and development. Naimah: So then, what would be a variant of uncertain significance? Helen: So, the output of that clinical scientist’s work looking at whether a variant is significant or not comes out into five categories, but three main groupings. What we’re looking for obviously through doing genetic testing is to try to find a diagnosis for somebody, and a diagnosis would be a place where we are confident that that variant impacts on that gene and leads to the condition that that person is presenting with. So, that would be a diagnosis on one end of the spectrum of what we might find. On the very other end of the spectrum are variants that don’t make an effect on the gene, that would...
