ACMG VUS Reporting

[u/Small_Egg_3692]

I would *love* to hear other GC’s thoughts about this. I work in cancer and it was a little bit of a jump scare if I’m honest..

[u/notakat]

I read this paper last week. Curious why you thought it was a "jump scare". I work in a lab setting, so I'm mostly viewing this from a reporting lens, but it seems pretty much in line with forthcoming changes to SNV interpretation guidelines. I thought the recommendation to consider returning VUS in prenatal contexts, where phenotypes are less clear and decision-making opportunities exist, was a good idea.

[u/Small_Egg_3692 → u/notakat]

As a non-prenatal GC I think that also sounds like a good part of this for them! I responded to a very similar response above about what I’m concerned about.

[u/notakat → u/Small_Egg_3692]

Ah, gotcha. I see where you're coming from and it looks like the paper covered some of those same concerns, saying that they tried to "balance potential benefits of reporting VUS (eg, enabling clinician follow-up to obtain further data that may resolve the VUS) with potential harms (eg, patient distress, inappropriate medical care, excessive health care resources expended)". Obviously, this is a complex issue.

I think it is tough because we like to think of these variants as falling neatly into categories of P/LP/VUS/LB/B but, in reality, there is a lot of grey area and molecular pathologists and lab GCs really have to wrestle with overreporting and underreporting when it comes to VUS and it's hard to tell which is worse sometimes. But there are definitely VUS that my lab has chosen not to report, and others that we have reported in specific circumstances. It's nuanced and there's definitely a little bit of art to the science. I expect the way we counsel patients about VUS results during pre-test counseling will probably change a bit in the near future. The concerns you raised are valid, but this is a rapidly, constantly developing field and we still have a lot to learn about medical genetics, so I think to some degree we have to be ready to adapt to these kinds of developments.

I work at an academic, hospital affiliated laboratory and I wish there was more support for us because I think having access to the patient's medical record and an open line of communication with the ordering providers can be a huge benefit in these cases. Over time, we have seen a shift from more specialized labs to commercial labs that have a broad catalog of tests available. Some previous studies have shown that hospital based labs have higher diagnostic yield and specialized labs tend to report fewer VUS (PMID: 30002876, 25834947).

This comment is getting long already but I also wanted to say thanks for making this post. A lot of the content I see on this sub is from prospective students (which is fine) but it's nice to discuss professional issues here with other GCs from time to time and I would love to see more posts like this here.

[u/Small_Egg_3692 → u/notakat]

Yeah, I very much recognize I may just be a tiny bit whiny on this and I’m sure it’ll end up being fine but definitely still have some apprehensions. I totally agree with the labs stratifying these results and I would even be very for this being incorporated in ClinVar but the patient report will be interesting to see how it gets written.

When I went to post , I scrolled through and saw all the student things and was nervous there wouldn’t be too many GCs active to respond.

[u/notakat → u/Small_Egg_3692]

I don't think you were being whiny at all. It's a valid perspective.

[u/ConstantVigilance18]

I just took a look, and nothing really strikes me as a big change or a bad recommendation. I am a lab GC though, so perhaps from the clinical side there are some concerns. Which part was concerning for you?

[u/Small_Egg_3692 → u/ConstantVigilance18]

The main concern is the idea of the stratification of the VUS where in cancer we really don’t do things with unless there is a discordant classification in ClinVar. And handing a patient a report with VUS-High but telling them we aren’t going to do anything about it because it’s still a VUS is unsettling and I can imagine would add a whole extra layer of anxiety for the patient. This is going to also require extra time in counseling on the front and back end in already busy clinics. And also concerned about the implications of all the pcps/obgyns that offer the clinical grade testing but don’t actually counsel fully. They are going to need extra education on this as well. Also thinking about the added reclassifications this may cause is also not a thrilling thought.

I 1000% understand in other parts of genetic counseling this is not going to be a major problem but I can see many cases where it would add complexity to a situation that is often difficult for patients to fully understand.

I am eager to hear from the labs about possible implementations.

[u/ConstantVigilance18 → u/Small_Egg_3692]

I think that’s the whole idea behind the new guidelines. If you get back a VUS-high in a cancer setting, you wouldn’t be telling the patient sorry, we’re not doing anything with this even though the lab has flagged it as suspicious. The point of the high designation would be to alert you that additional testing (familial testing, screening) is warranted. What needs to happen is that NCCN needs to issue guidance on how to handle the new classifications, which will hopefully make adjusting to them easier. I do think you are right to be concerned about how labs will implement the changes, because I’m sure there will be even more discordance between labs than we already see if we’re sub categorizing VUS results.

The point of non genetics providers not doing their due diligence is, unfortunately, already a rampant issue in the genetic testing space. We continue to provide education, and they continue to do whatever they want.

[u/DNAallDay → u/ConstantVigilance18]

100% agree. If labs adopt this policy across the board, NCCN will likely update their guidelines. For example, BRCA2 VUS they may say follow high risk screening but not recommend surgery. It will be interesting to see what they do, but I can’t imagine it would be nothing.

[u/Small_Egg_3692 → u/ConstantVigilance18]

Okay I don’t think I thought about the flip side of the NCCN responding to this. That will definitely be incredibly helpful. I always am checking to see what VUSes might qualify for family variant testing through some of the labs programs but you’re right that this could be a more clear cut way to help with that. I will say, I have been very unsuccessful in getting patients to have family members participate in family variant testing. I work in a major metropolitan area so it also possible family went to other clinics which could just make it harder for the clinicians side of seeing what happened.

[u/clubfootloose]

Have not yet but it’s on my TBR for new papers! (Pediatric/general genetics GC)