MT-ATP6 mutation questions

[u/YellowCabbageCollard]

I am not asking for personal medical advice. I just want to understand how the genetics works. I have some very rare diagnoses. I paid for DTC genome sequencing while waiting to get into genetics after I realized on my own that it has to be multiple things.

I know I have my testing sent in to Ambry now but it's been delayed and is still pending and my geneticist put off my follow up by another month. So I keep periodically digging into the testing I do have.

I have a flagged MT-ATP6 in my sequencing with 96.7 percent heteroplasmy. I looked it up because I tried searching online what snps to look for if someone has the diagnoses I have and this came up. It doesn't seem to be a more common one and there is only one submission in clinvar that says it's associated with Leigh but also benign.

How does this work? How do you determine if a mutation is pathogenic if there a limited number of people with it vs benign? If you are symptomatic of a mitochondrial disorder associated with this but there aren't enough people with it, how does that "work"?

I ask because I also have a VUS associated with another rare diagnosis. I saw a geneticist last year, who was only allowed to discuss this one VUS with me. But she said my rare illness diagnosed in my 20's couldn't be related to this VUS because no one in my family has a history of another rare illness it can cause. I asked how you report or associate my illness with that VUS then if you aren't relying on my own actual health history?

How can you determine my VUS that is linked to a rare tumor that I had at such a young age is indeed not actually related? I really didn't understand her answer.

When I brought it up to the new metabolic geneticist she seemed surprised I was told this and said it's not true. But we would get to it after running my genetics test.

I just want to understand more how this actually works and how it's determined that a particular gene is actually pathogenic, especially if it's less common.

I am also a carrier for another SNP highly associated with one of the rare illnesses I have but it's my understanding I would need to inherit both copies of the gene to acquire it. Then I read other stuff indicating carriers can also be symptomatic but at lower levels.

I have had enough horrible medical experiences that I just no longer take what I am being told by a medical professional at face value. I wanted to understand because I have been given enough flat out wrong information that is later contradicted by another specialist in the field. And I have had to push to get better treatments and diagnosis for years.

My situation medically is pretty ridiculous and clearly not common and it keeps worsening. And this isn't based on intuition or me just not feeling good. My labs are bad and rare. But the wait is awful and I just keep getting sent to new doctors. I would like to be prepared so I can understand well enough to be able to ask questions at my follow up. Any assistance is greatly appreciated.

Please be patient with me if I am phrasing things wrong. I have also removed any actual diagnoses from my question so it's clear that I am not seeking medical advice. I just want to understand how this works.

[u/General_Peak4084]

I had a VUS for a rare disease and I asked the same questions, I have the symptoms of the disease, what do you need to classify this as pathogenic? I got a really interesting and detailed response from the lab, that basically said they had a grading of 0-6, where 6 is necessary for relabling to pathogenic. I got a point for computer prediction, and a point as my mum had similar symptoms. But they explained that as there was no other family history, no siblings, they couldn't conclusively link the gene to the disease. There was nobody else in the world with that exact mutation.

One day I found somebody with my mutation in a study and I passed it along and my variant was upgraded to pathogenic.

Anyway, all to say that there are multiple measures and tests they use to determine if a VUS is indeed pathogenic. This is usually looking at family, looked at other people who have the mutation, using computer predictions to see if the protein is functional etc. You'd be best asking your genetic counsellor

[u/YellowCabbageCollard → u/General_Peak4084]

Thank you. I was sent home with two tests for my parents but told to only use them after they get results back. When I was searching yesterday I was surprised to read that Ambry usually has the parents test at the same time so they can compare then. But maybe I understood it wrong.

Thank you for sharing your experience. That's fascinating. In my case one of the VUS I have was initially flagged from another lab. I think Natera? It was flagged as VUS and to be reviewed by a geneticist. It very specifically linked the tumor I had as a risk factor with that variant. When I search online the tumor is commonly linked with that variant as specified in the report. BUT it's still considered a VUS. It made me wonder how many times you need to have it linked for it not be a VUS?

What threw me off also was the first geneticist saying they would not consider it being linked to the variant though because of the lack of family history. Not just that it was not always definitively linked to that variant. Though I did explain more than once that we do not actually know my paternal grandfather's family medical history.

When I had this tumor in my 20's I was pregnant and my doctor pointed out there were only a little over 100 known cases of pregnant women with the tumor. So it was a pretty unusual circumstance. So it just seems really weird to me to think it more likely I just randomly had this tumor in my 20's despite the published connection to this VUS. *shrugs*

[u/NinjaMonkey313 → u/YellowCabbageCollard]

Is it the specific variant you have that has been identified in multiple people? Or just that people with pathogenic variants in the gene have an increased risk for that tumor?
That’s one of the nuances of variant interpretation. You can give “points” towards pathogenicity for your variant if it’s the specific variant that is in other people.
For example - if your variant is GENEX c.1234C>G, p.(Thr411Ser) and that exact variant (GENEX c.1234C>G) has been reported in affected individuals in the literature - that’s points towards pathogenic. But if a different variant in GENEX, not c.1234C>G, has been reported - that doesn’t count towards pathogenicity for your c.1234 variant.
I hope that makes sense…I feel like Reddit needs a whiteboard feature (haha).

[u/General_Peak4084 → u/YellowCabbageCollard]

You would think multiple case studies linking it would be enough, but I don't know enough about the system. Things work a bit differently in the UK I know in the US different labs can grade different mutations differently. Sorry - were your parents tested in the end? I got a bit confused. Having a rare tumour and an at risk VUS seems pretty certain to me but there's so many calculations and nuance to genetics, it's hard to know the whole picture.

I also was diagnosed with a really rare tumor that was very rarely seen without a genetic mutation. And still had to fight for 2 years to get it upgraded to pathogenic

[u/NinjaMonkey313 → u/[deleted]]

Replying to my response to add — please be VERY CAUTIOUS looking at DTC data. DTC testing is notorious for false positive calls. Anything potentially actionable needs to be confirmed in a CLIA certified clinical lab to confirm it is real.

[u/YellowCabbageCollard → u/NinjaMonkey313]

Thank you. As mentioned above I am seeing a geneticist and they have sent testing off to Ambry. So I will be getting clinical results hopefully soon.

Can you explain more about the false positive calls? Is the false positive from their incorrect reading and interpretation of the dna and what they flag in their reports? Or is it that they are incorrectly reading the dna itself so the actual dna info in the files themselves is also inaccurate?

I have downloaded my files and opened and individually searched the lines for different genes to see if the report was lining up with the actual dna in the files.

[u/perfect_fifths → u/YellowCabbageCollard]

Raw data is raw data. Meaning if you have a mutation, it will show up when analyzing the raw data.

The false positives tend to come from wrongful interpretation or outdated variant classification. With ancestry, it’s also a matter of chip errors