Helen Brittain: Genomics 101 - What is a variant of uncertain significance?

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 download the transcript or read it below.


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 be benign. We would call
those harmless variants, things that don’t change the gene and
wouldn’t be expected to be associated with a
condition.  


And then, in life there’s always a grey area, and the part in the
middle, between being confident about a diagnosis on one end or
being confident that that variant really doesn’t impact the gene
and is harmless. We have variants that we find that we do not yet
understand, and that’s basically because our knowledge as of when
the variant is looked at is good, but it’s not perfect. There
could be more to learn about particular variants or particular
conditions, but at the moment we just don’t have enough
information to be sure one way or the other. And that’s really
important, we’ve got to get it right, so we do have this grey
area in the middle, which are the variants, differences in the
gene, where the significance of them on that person is
uncertain. 


Naimah: How often do we find these variants of uncertain
significance when we’re trying to genetically diagnose
patients?  


Helen: They are relatively common for us to encounter, and that’s
for a number of reasons, I would say. I think that we know a lot
about our genes, and our knowledge has come on leaps and bounds,
and it’s still improving at a rapid rate, but we don’t know
everything yet, so there will be areas where we haven’t met a
particular variant before, or we can’t predict how it might
affect that gene, or there’s some uncertainty about it because we
don’t have full knowledge yet. So, it does happen relatively
commonly, and it probably happens more commonly the more genes or
the more information we’re looking at. So a test looking across
someone’s genome, like whole genome sequencing, we’re more likely
to come across these things than if we’re doing a very targeted
test looking at one specific gene that we understand very well,
for example. 


Naimah: And how can knowing the significance of a gene variant be
impactful for clinicians and the patient? 


Helen: This is really important, knowing the significance of a
variant is key. It’s fundamental to genetic testing, because we
are trying to make a confident diagnosis for somebody, and we
have to get that right, because if we make a diagnosis in
somebody there are lots of knock-on implications of how that
information is used to inform the healthcare of the individual
who has the condition, or maybe even to inform their family
members, who could be at risk of the same condition. Obviously,
we share our genetic information amongst our families, and so a
genetic test might be used for a family member as a result of a
diagnosis in one individual within their family.  


And of course, in some situations, that might lead them into
either needing screening for a particular condition that could
happen, or being removed from screening if they don’t have the
genetic cause within their family. Equally, people might make
choices surrounding whether to extend a family or reproductive
choices around the knowledge of a genetic condition within a
family. So you can see, the implications are huge. It’s really
important this is correct.  


Naimah: And finally, I just wanted to ask, can we reclassify
variants of uncertain significance? 


Helen: Yes, there’s real need to do this because people are
wanting genetic diagnosis answers for understanding, and for all
of the implications we just mentioned about why are diagnoses
important. So yes, we can reclassify variants of uncertain
significance, and that can happen in different ways. It’s not
always possible straight away, unfortunately. So, what we often
need is time, and that is time to understand that variant a bit
better, and that might be through seeing it again in other
people, maybe who have the same pattern of health problems or
same picture in terms of their rare disease, and we start to
understand, okay, that might actually add up to suggest that that
variant is affecting the way that gene is working. Or equally, we
might see it in other people who don’t have the same rare
disorder, so we’re starting to see, well actually, maybe it’s
harmless and it’s just part of the natural genetic differences we
all have. 


The other way that we can understand variants of uncertain
significance better would be through research, so for example
researchers looking at designing studies to try to see if they
can make a model, for example, with an animal who might have the
same type of variant, and see if that causes an effect on their
health, so learning specifically about that variant through
research could also help. And there are things that clinicians
also actively try to do, and this is why we work together with
the clinical scientists is to understand, are there other people
within the family with the same rare condition, and would it help
to test them to see if they also share the same rare variant. And
sometimes that can help, not always. So yes, we really want to
try to reclassify variants of uncertain significance, and as far
as possible, we will, but sometimes they do just need that time
for us to build that bigger picture. 


Naimah: That was Helen Brittain explaining variants of uncertain
significant. I’ve been your host, Naimah Callachand, and if you’d
like to hear more explainer podcasts like this, you can find them
on our website at www.genomicsengland.co.uk. Thank you for
listening.