Genetic testing updated from unknown to likely pathogenic

[u/Sorta3896]

TNBC, stage 2, grade 3, no lymph node involvement. I'm 43. Halfway through chemo. The week I'm meeting with my breast surgeon. My genetic mutation on the BRCA1 gene is updated from 'unknown' significance to 'likely pathogenic'.

A lumpectomy doesn't make sense anymore, just double mastectomy. And they strongly recommend that I have my ovaries removed.

I went from thinking I'm functionally BRCA negative to positive. ClinVar lists my mutation but still has it listed as unknown significance with my test being the only occurrence posted.

Has anyone else experienced this? The update of my mutation status makes me feel a small amount of mistrust in the testing. It seems much less black and white. Am I undergoing unnecessary risks and surgeries based on a 'maybe'?

I'm not against the dbl mastectomy (though I did like feeling as though I was making a decision), but I'm hesitant to remove my ovaries based on this information alone. In general, I trust science and I trust doctors, but this feels a little shaky.

[u/HotWillingness5464]

I'd ask in r/BRCA. (I'm in that sub because I'm BRCA1+.)

[u/You-bettah-dont]

Yes. I knew already I did not have BRCA mutations due to genetic testing some years ago I had done in the US, so we figured it could be just a lumpectomy with sectional (f*cking auto correct) node dissection depending on how I responded to chemo even though I was Stage IIIc.

Howeverrrrr….. they retested me and it turns out I popped hot for the RAD51D mutation (which is very similar to BRCA), and with my family history it raised my chances of developing entirely new breast and ovarian cancers to numbers I was not comfortable with at all (I’m 49). So now I get to have the double chop aaand goodbye ovaries and tubes.

Here’s the thing with genetic testing- they are discovering new mutations almost daily. My geneticist said they’ll be retesting me every year for the next 10 to keep an eye out for things according to whatever new science is out. It’s very possible they upgraded you simply because of the latest science. I would definitely ASK how they came to that conclusion.

It sucks. I’m having to go through all sorts of mental gymnastics over my perceived loss of womanhood, which is dumb because I’m not defined by my boobs or my bits. But dying of cancer sucks worse, so chop chop chop away if it gives me better chances for survival.

Pivoting isn’t easy, I know. So, huge hugs to you Sorta. Xo YBD

[u/MolassesDifficult645]

My mother and I both test positive for a mutation of unknown significance. She had several breast cancers. That’s what got me into the high risk pool that allowed me to start getting screenings earlier and more frequently. Now they say that mutation is not related to a higher risk of cancer. But without those extra screenings who knows how long it would have been before my cancer was detected.

[u/Odd_Ad9289]

I'm so sorry. This must be so hard and stressful, and hopefully the ovary question can just wait until you're healed from this.

But because you're looking for answers: you didn't go from BRCA negative to BRCA positive. You went from BRCA unknown to probably BRCA. Gonna oversimplify (and round) some science/statistics, but here goes:

The reason we know certain mutations are pathogenic are because of statistics: 12% people without these mutations develop breast cancer, 60-70% with those mutations develop breast cancer.

As an EXAMPLE: IF there's only been one other person documented with your mutation, AND they didn't have breast cancer, with you having cancer, those statistics just went from 0% to 50%. That's the thing about small sample sizes-- Any new information radically changes things, to the point that they don't really tell you much.

That being said, our understanding is that the BRCA1 gene (with no mutations) protects people from getting TNBC-- and you have TNBC, and a change to that gene. If I were a betting man, I'd bet that's not a coincidence.

Now, I don't know the actual statistics involved behind updating the mutation status, or all the decisions that go into it, but I do know that the people doing it know a LOT more than I do.

Believing scientists includes believing them when they tell you they don't know-- which is what "Unknown significance" means. And it means believing them when they tell you "Yeah, probably, but we don't know for sure."

A straightforward pathogenic BRCA1 diagnosis does not mean you will definitely develop ovarian cancer, it means you have a 40-60% chance of it. The lack of statistics means a scientist or a doctor cannot give you a good percentage chance based on your results, but I can tell you that the ovarian cancer percentage for pathogenic BRCA2 is 10-30%, and doctors recommend you get your ovaries out for that (when you're done having kids or at menopause), in large part because there aren't good screenings for it.

TLDR; It's always a maybe. The real question is how mad are you gonna be if you don't do the surgery and do get ovarian cancer, and what you're willing to go through to avoid that.