How to get definitive BRCA results when current tests are limited?
July 4, 2017 9:53 AM   Subscribe

Based on family history, my genetic counselor has told me that my family has a BRCA mutation -- the kind that doesn't show up on the current tests. As a result, I'm in a position where I have to decide whether to get major, life-altering surgeries without knowing whether I have the mutation. Is there somebody, somewhere who could determine whether I'm positive -- possibly by sequencing my genome?

Given my family's history with cancer, the genetic counseling team at my healthcare provider has determined that we carry a BRCA mutation. Unfortunately, our mutation is not detectable by the current test(s?) for BRCA, which is true about 10% of the time.

That means that I *could* have an extremely high risk of getting breast cancer and a substantially high risk of getting ovarian cancer. (The risks are so high that many women who test positive for the mutation get their breasts and ovaries removed, which I would choose to do as well.) On the other hand, I might not be. I have a 50/50 chance. Currently, I'm in a position where I have to decide whether or not to get major, life-altering surgeries without knowing whether I have the mutation.

My question is, is there any way I can find out if I'm positive or negative? Is there somebody, somewhere (for example) who could sequence my genome?

Thanks much.
posted by MelanieMichelle to Health & Fitness (13 answers total) 6 users marked this as a favorite
To make sure I'm understanding, your family history is suggestive of a BRCA change but no one with actual BRCA has had a disease causing variant identified (the 10% number you reference)? Or only you've been tested and you had no variant found (which means you could be positive or negative but there's no way to tell without knowing the familial variant-the 50% number you reference)? And the testing ran so far has been inclusive of a wide range of genes associated with BRCA or only the BRCA1 and BRCA2 genes?

So ultimately yes, you could do genome/exome sequencing but the likelihood of additional value might be limited depending upon what information is already known. Your GC should be able to help you find such testing and go over the costs, benefits, risks, etc with you. If not, you need a different GC.
posted by beaning at 12:06 PM on July 4, 2017 [1 favorite]

Best answer: Yes, there are many diagnostic tests that sequence ALL the exons of BRCA to give comprehensive results. As a cancer genomics researcher, I'm rather surprised that the genetic counselors that you're speaking with didn't offer these to you. You should go back and request a more comprehensive test, and if they're unaware of them or unwilling to refer you, you should seek out a different counselor.

Some more background that may help you: BRCA1 and BRCA2 mutations are by far the most common cause of hereditary breast cancer, but there are other mutations in related genes that can produce a similar predisposition to breast/ovarian cancer. There exist a spectrum of sequencing tests, from those that only look at the most common BRCA1/2 mutations (which it sounds like your family has tried) all the way up to sequencing your whole genome (which is probably unnecessary at this point).

If it were my wife or mother, then I'd certainly get at least the comprehensive BRCA1/2 test done, preferably on both you and one of your family members who has been affected. Having a known positive relative could be important, because if you identify a mutation in them, but not you, you'll know that you're in the clear. If you both come back negative, though, it might suggest that a rare mutation in another gene is to blame and would steer you towards a more comprehensive test as a next step.

I am not a genetic counselor, and cannot offer specific medical advice, but I am an expert in generating and interpreting cancer genome data and would be happy to answer more questions on the general science behind of this all. Best of luck to you and your family!
posted by chrisamiller at 12:12 PM on July 4, 2017 [10 favorites]

Response by poster: Thanks immensely to both of you. I'm already feeling more hopeful, and @chrisamiller, your offer to answer questions gives me considerable relief.

To clarify, here is what I know thus far:

Many of my family members on my father's side have had breast or ovarian cancer, and some have had multiple cancers. Two people have had melanoma, the risk of which is apparently increased by BRCA2. Also, the cancers have occurred later in life than cancers typically connected to BRCA1, so it may be more likely that we have BRCA2.

Only two people (who are still alive) were willing to get tested: my father's sister, who has had breast cancer and ocular melanoma, and my father, who has had melanoma. Because neither my aunt nor my father was willing to go through their healthcare providers, we used, doing whatever panel they offer. (I don't know what that is.) My aunt's panel came back negative. My father's panel hasn't come back yet (it was lost and has to be redone), although given that my aunt's came back negative, I suspect his will as well? Maybe? I have not yet been tested.

My genetic counselor is telling me that her team has looked at my family history, and based on that history, they believe that we are positive for a BRCA mutation. (I asked whether it could be a non-BRCA mutation, and she said no. Not sure how she is able to say that.) She is also telling me that the mutation we have is not detectable in tests.

That's what I know. I would be so thrilled to hear that it's possible to get definitive results through other tests. I do not want to get a double mastectomy if I don't have to!

Thanks again!
posted by MelanieMichelle at 12:30 PM on July 4, 2017

Response by poster: One more clarification: My counselor has said that the current tests for BRCA identify 90% of BRCA mutations but can't detect 10% of them. She believes that my family is in that 10% -- i.e., we have a BRCA mutation that can't be detected by the test.
posted by MelanieMichelle at 12:53 PM on July 4, 2017

I think you need to talk to some other medical professional, because your genetic counselor sounds really confusing. If you're negative for the BRCA 1 and 2 mutations, you're negative for the BRCA mutations. There are other genetic mutations that are known to increase your risk for breast cancer, but they are not called BRCA, and are also testable - I know women who have had breast cancer and do have some of those lesser known mutations. They found out they have the mutations via a genetic test, not by someone making guesses based upon their family history.

In short, this lady sounds like she is confusing you, and for good reason. From what you're saying here it sounds like she's basing her conclusions on conjecture and is not being very clear with you about where those conclusions are coming from or what your options are for real, scientific testing. If I were you I would get a full genetic panel before I worried much about this. You can get one from a company called Myriad Genetics (and probably others, but that's the one I know about). It is expensive - they charge insurance companies $6700 (or at least they did 2 years ago, when I had it) - but if your insurance company won't pay for it, they only make the patient pay a few hundred bucks.
posted by something something at 1:04 PM on July 4, 2017 [4 favorites]

Response by poster: Thanks, something something. But I think it might actually be true that the BRCA tests aren't always conclusive. Here's a paragraph on the website of an organization specifically for BRCA folks:

Improvements in Testing Technology

In the past, some tests failed to identify certain BRCA1 and BRCA2 mutations known as 'rearrangements' as well as other mutations. Some families that previously tested as "uninformative negative" for BRCA in the past may benefit from expanded panels that look for newly identified BRCA mutations. The "BART" (BracAnalysis Rearrangement Test) is a panel that looks for specific rare genetic mutations known as "large rearrangements." BART testing is usually recommended in families that have a suspicious history of cancer but no identified mutation on comprehensive BRCA testing. Families from certain ethnicities including Latin America, Caribbean, and Near and Middle Eastern background are more likely to test positive for a BART mutation.

I just sent my counselor an email asking about the BART test (although given that my family is Ashkenazi Jewish, I'm not sure how relevant it'll be). But the above paragraph seems to leave room for other mutations that the test can't identify, i.e., "Some tests failed to identify certain BRCA1 and BRCA2 mutations known as 'rearrangements' as well as other mutations."
posted by MelanieMichelle at 1:19 PM on July 4, 2017

It's definitely true there's a lot we don't know about how genetics influences cancer risk. I was negative for all known breast cancer mutations but positive for familial melanoma, which is what killed my father. There aren't any large scale studies investigating a connection there but I do wonder, given that I was diagnosed with breast cancer at 38. Still, I would absolutely get a full range of the available testing done before you even consider a mastectomy.
posted by something something at 1:22 PM on July 4, 2017

There are instances of breast, ovarian (of which both my grandmother and 40 yr old sister died from), colorectal and melanoma cancers in my family - all on my mothers side. Because of the extensive history of cancer in my family, it was recommended to me that I have the BRCA panels done. However at the time it was very cost prohibitive for me so I declined. I am glad I did because the following year my insurance actually started covering a portion of the testing costs - not just for the BRCA tests but for other genetic testing. So, I went through Myriad and got a whole panel done and it was found that I have Lynch Syndrome. Point of my story - I'm glad I wasn't able to have the BRCAs done previously because those would have come up negative and we'd all have shrugged our shoulders as to why the women on my mothers side kept getting life threatening cancers and we would have never known about the Lynch. I would never have had my hysterectomy that most likely has saved my life. Don't discount the testing that covers more than the BRCA. There's valuable information to be had there.
posted by Sassyfras at 3:04 PM on July 4, 2017

Questionable interpretation by the counselor of your family's "results?" Ashkenazi heritage? Melanoma + breast cancer on your paternal side?

All of this and your GC seemed to just sort of throw up their hands is VERY concerning to me. I also recommend finding another GC in your area, if you can.

Most sendout genetic labs (Myriad included) now have a "billing department" that will do the preauth to your insurance company. They generally set an out-of-pocket dollar amount ($100-$200) and tell you that if your cost is at or below that number, they'll run the test and continue to fight to get the difference from your insurance company. If it's above that, they'll call you and tell you the exact amount you will have to pay out-of-pocket. In the last 12-18 months, most private insurance companies have become much more accepting of MOST genetic testing (not all). But particularly, there's a wholesale acceptance of breast cancer genetic testing (BRCA, BART, etc.) by insurance companies, especially in light of the Supreme Court decision that stopped Myriad from "patenting" a gene.

Source: I run the office for a hospital's Genetics Clinic. Please MeMail me if you have other questions or even want me to put you in touch with a GC, even if you're not in our area.
posted by kuanes at 4:16 PM on July 4, 2017 [3 favorites]

Is there a reason you can't go to a different genetic counselor (aside from the PITA factor of going through your whole history AGAIN)? Like, is there only one such provider in your area?
posted by wenestvedt at 7:16 PM on July 4, 2017

Response by poster: Wow, I continue to be grateful for these excellent responses, and I will likely MeMail a couple of you, yes.

Another clarification: I'm not dealing with an isolated GC. I'm dealing with a GC who has consulted with her department at a major HMO and is following their protocol. A friend of a friend who works in cancer genetics (and whom I have yet to talk to, but will) has told my friend that my HMO has a lot of data, and that they therefore might have a solid genetics counseling program.

Identifying a family as HBOC (high-risk for breast and ovarian cancer) based on history alone is a new thing that this HMO is doing, presumably because of the data they have. Identifying *my* family as a BRCA family is, I'm now remembering, a result of our Ashkenazi Jewish heritage. (I think my counselor said something to the effect of, "The BRCAs are the mutations that Ashkenazi Jews carry.") So it may well be a new and viable approach? I have no way of knowing.

What is most important to me is, obviously, getting an actual result re: BRCA and any other breast/ovarian mutation so I can make an informed decision about whether to have surgery (and any other care protocol).
posted by MelanieMichelle at 7:16 PM on July 4, 2017

Response by poster: Another update for those following: My husband called Myriad this morning, and they confirmed everything my GC said:

1) Given my family history (high incidence of breast/ovarian cancer and melanoma in multiple generations), plus the fact that we are Ashkenazi Jews, we point "very strongly" to having a BRCA mutation;
2) While they can run panels for mutations other than BRCA, it doesn't make much sense to do so in my case, because among Ashkenazi Jews, 99% of ovarian/breast cancer mutations are BRCA;
3) Current tests can detect most but not all BRCA mutations.

In other words, I'm exactly where I thought it was. I have yet to meet with the high-risk team at my HMO, so we'll see what they do and don't recommend re: surgeries and surveillance.

Thanks again for your help, folks -- and please feel free to continue adding if you know something beyond what I do.
posted by MelanieMichelle at 11:27 AM on July 5, 2017

From some googling, it appears that Myriad offers several different BRCA tests with different levels of coverage - do you know which one was performed?

Yeah, it's certainly possible to have mutations that are missed by the panels. I don't know how much background reading you've done, but there are "point" mutations, like single-base changes or small insertions/deletions that should be easily picked up by this kind of testing. There could also be larger rearrangements of your genome that break the gene or delete one copy. These could be missed by a focused panel test. It does appear that in their more comprehensive BRCA test, they have the ability to detect some small fraction of large events, but not most of them.

I don't know a lot about the specific population genetics in play here, but their statements about Ashkenazi heritage and risk make sense on the surface, anyway. Another commenter in the AskMe thread mentioned Lynch Syndrome, which is an inherited mutation in another gene called TP53. I don't think you can completely rule out some other event like that without a more comprehensive test, but the population genetics in play can certainly inform the likelihood of various events, and BRCA mutations of a few specific types are very common in the Ashkenazi Jew population. (But I am unclear which of those would and would not be caught by the test you had!)

Whole-genome sequencing would be one way to detect a more complex event, but it's unlikely to be covered by insurance, and may require some expertise to interpret. They can be fairly expensive from some providers - in the 10k range. Much of that cost is in the analysis and interpretation, and the "raw" genome costs might be closer to 1-2,000 dollars.

Hope this helps with the technical side of things, and really hope that you're able to find some certainty to help with your decision!
posted by chrisamiller at 5:49 PM on July 5, 2017

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