BRCA1 variant of uncertain significance and removing ovaries

chinadollmom

I have a 'variant of uncertain significance' in BRCA1. I had bilateral BC, one of which was triple negative. I have a lack of female relatives -- no sisters or aunts and one grandmother who died young from other causes -- so it's hard to say if ovarian cancer runs in the family or not. I strongly suspect the variation is from my paternal side (with the grandmother who died young), since 3 of the 4 people with the variation have the same ethnic background.

My radiologist suggested that when my treatment was all over, that I have my ovaries removed. Her rationale is that since I was triple negative and bilateral, I was relatively young when I was diagnosed (49), I'm now post-menopausal, and ovarian cancer is so hard to detect, it would be on the safe side. The genetic counselor, however, didn't think that I should take any action whatsoever based on my gene test result. I have yet to talk to my BC oncologist or a gynecological oncologist, but it already looks like there will not be a concensus.

I was all for removal until I started researching the side effects, and now I'm not so sure. I would appreciate any information, experiences, or opinions.

in_cognito

Have they offered BART testing for you?  I too, am BRCA 1 unknown variant seen in 33 families.  I have no history of ovarian cancer in my family on both sides that is known.  I do have a history of pre-menopausal BC on my father's side.  I had BART testing done and it came back negative and the genetic couselor said from an ovarian cancer standpoint it probably was not necessary to remove my ovaries.  However, my Onc wants to remove them to shut down the estrogen.  Since you are triple neg, you may want to look into the BART test.  But be warned, I have since found out that my insurance does not cover this after being billed $700. 

Here is a link about BART.

http://www.ucsfhealth.org/common/pubs/primarycare/june2008/cancer_genes/index.html

chinadollmom

Thanks for the link. I had not heard of that and will definitely ask my doctors about it.

I noticed the link says the improvements in testing were developed in 2002 and 2006 by Myriad. I wonder if that testing has already been done for me, since Myriad ran my test test in 2009. I imagine the genetic counselor would know for sure.

Mutd

Each uncertain variant is different. Some are absolute unknowns, others may not have enough info but there are some hints about their potential significance. Most turn out to be totally insignificant, over time, as the data trickles in ... but a few prove to be connected to cancer.

 If you really want to take an uncertain variant into consideration (which isn't normally recommended but I undrestand that you couldn't find guidance in family history either) then you must research your specific variant. Google its name, dig deeper into the research papers, sometimes there are grains of truth. Remember, each variant is a special story. Your variant name is on your lab report.

And no, Myriad wouldn't do a BART testing on your DNA for free. That's generally reserved for women with very strong family history. All others have to request the BART test in addition to the conventional BRACA.

chinadollmom

Mutd, thanks for your informative response. I Googled the variant name (S708F) with 'BRCA1' also in the search. It found 2 long lists of someone's genome data on personal genome sites, but as far as I can tell, the S708F was not on the BRCA1 gene, and no other information seemed to be available.

When I Googled the whole name (S708F (2242C>T)), it did come up with something from the 'Werner Syndrome Mutational Database' at the Dept. of Pathology at the Univ. of Washington. But Werner Syndrome seems to be some strange disease not related to BC at all.

It looks like I have to educate myself a lot more before I can have any idea what I'm looking at. Any suggestions for where to start getting a more general understanding of gene analysis?

One other question:  when they say "No action should be taken on the basis of the variant of uncertain significane", do they mean SOLELY on the variant? Can the variant never be taken into consideration along with other data? My natural instinct as an engineer is to consider it along with the other data I have, but to give it less weight. But perhaps it's more correct to just throw it out completey, as if it were 'bad data'.

Annabella58

Hi, I am not BRAC and no family history, except for one aunt who died from pancreatic cancer (not genetic, alcohol related).

I had bc twice in the same breast.  I am the one who researched ovarian removal, as I was heavily ER+++.  I am 54(52 at the time of diagnosis with 2nd) and was nowhere near menopause.

You may wish to consider getting your hormonal levels checked, as you don't mention what age you are or if you are done having a family.  If you are very close to menopause, perhaps the ovarian removal wouldn't be necessary but that is a question for your oncologist.  Or even an OB/GYN oncologist I should think.

since the surgery, I am perfectly fine.  Some vaginal dryness, easily fixed.  Surgery was a piece of cake, it was my research and decision.  Interesting to note, that MSK in NYC uses ovarian ablation as one of their first lines of defense in ER+ cancers.

your skin will not look horrible, you may get some bone issues.  I am on arimidex already, so with the ovarian removal, I must have a big lack of estrogen, but I feel fine.  The SEs are nil, in my case.  Surgical menopause was easy....I was not in menopause, but the arimidex must have been suppressing alot already, as other than a few "warm ups", no big deal there.  I wouldn't read the horror stories that are out there.  They are out there because someone had a bad experience...the ones that did not would not post it.  So I do want to let you know that it can be a perfectly fine thing to do.  I do not regret it for one instant.  I feel such relief knowing that I don't have to worry about that as well.  Sex life was fine, just use something such as Very Personal moisturizer or KY sensitive jelly.

Good luck with whatever you decide, PM me if I can be of further help.

Mutd

Oh, Chinadollmom, I didn't notice at first that you're like 3rd or 4th ever to be found to have this variant, out of a nearly a million people tested. You're right, variants which are so rare are often invisible to the research community. The S708Fs you saw, they weren't even in BRCA1...

 "Can the variant never be taken into consideration along with other data? My natural instinct as an engineer is to consider it along with the other data I have, but to give it less weight"?

You can add a "generic" variant into the equation (without knowing anything specific about its potential level of danger); but it won't add anything substantial to your risk estimate. People speculate that 5 to 10% of the uncertain variants may be causing cancer. Take the highest estimate, multiply it by the highest estimate of ovarian cancer in a BRCA1+ woman, and the result is a pittance.

Research geneticists love adding all various factors together in multi-parametric models! This one is one of several good papers (picked more or less at random) if you want to get a taste of their models: http://www.ploscompbiol.org/article/info:doi%2F10.1371%2Fjournal.pcbi.0030026

Clinical geneticists, not so. The FDA is reluctantly staying away from tests like BRACAnalysis, because their results are pretty much binary. Like, mutation or no mutation. No complicated algorithms, nothing a doc shouldn't be able to grasp. But multivariable models, they're a fair game for the fed regulators, they need a validated statistical proof to be allowed into clinical practice. It'd take the same hundreds millions $ it takes to test clinical drugs. So the complicated models remain, mostly, the stuff of academic publications. And the BRCA test results stay formally the same binary (yes, no, or sometimes bad data like in your case)

One of the most popular research methods to guess the significance of an uncertain variant is to look for the same gene in other species. There are many flavors of this "species conservation" method. Most would agree that S708F shouldn't be a big deal. Like this 2007 table lines up BRCA1 proteins from a dozen of species: http://agvgd.iarc.fr/BRCA1_Align.htm

If you scroll to 708, you'd see that many living creatures "spell" this segment of the protein differently. The dogs actually have F there, where most humans have S. If pretty much everything goes there in other species, and if F specifically works fine in one of them, then chances are that the change from S of F in our species is OK too? (Since 2007, many more species have had their genomes studies, and several more turned out to have F708's in their BRCA1 genes too).

It is correct that a bilateral triple negative looks like a BRCA story. And in your family with too few female relatives, lack of family history may not be enough to dispell the suspicions. But if there is anything wrong with your BRCA1 gene, then most likely it isn't this one misspelling at position 708. Maybe something which only BART could find ... if there is anything to be found at all.

chinadollmom

Really interesting information, Mutd. It will still be a tough decision, but I feel like I at least have a clue about my variant of uncertain significance. Interesting, too, about genetic models and the FDA. Thanks so much for your responses.

I also appreciate your post, anniealso. It's reassuring to know that having your ovaries removed is not usually not such a bad exerience. I'm 50 now and on tamoxifen, but I haven't had a period for over a year. Considering that and that my family is done, it doesn't seem like it would have that much effect on me.

westiemom

chinadollmom, this is no doubt a difficult decision. i'm brac1+, had a bi-lateral mastectomy and really fought removing the ovaries, (i'm 47) i've not had a period in well over a year when i was diagnosed in february. had mastectomy in april, chemo may thru august, and oophrectomy in september. although i had bloodwork, vaginal ultrasound and all showed healthy ovaries, my pathology after the ooph found dysplasia on both fallopian tubes, this would have never been detected, so i'm grateful for removing the fallopian tubes and ovaries. the only side effect are the hot flashes which i was already experiencing. since the oophrectomy i've been taken off tamoxifen and now on arimidex - no side effects thus far. i hope this helps. take care.