BRCA 1 of unknown clinical significance

in_cognito

BRCA 1 of unknown clinical significance

in_cognito

Does anyone have this and know what it really means?  I just got my results via the phone - waiting for the hard copy in the mail.  I've googled information for this but still unsure on what it really means. 

GC1

Hi in_cognito

A variant of unknown clinical significance is a change in the gene in which it hasn't been determined whether this gene change is associated with a higher risk for cancer or not.  It is sort of like finding a spelling mistake in a word.  Some spelling mistakes make the word and sentence unreadable, while others don't. 

Often the specific change has been seen so few times that very little is known about the change. Over time and with more families tested, this change will be seen again and the lab may be able to determine whether the change is a mutation (causes an increased risk for certain cancers) or benign. 

Have you met with a genetic counselor to discuss your family history and these results?  They may not be able to provide you with all the answers you are looking for as this type of result often leaves much uncertainty but they can provide you with information about these genes and the test result.   

JennyB100104

Hi in_cognito: I have a BRCA2 mutation of uncertain significance. It's so frustrating to know you have a mutation and not know whether it could be the cause of what we're going through. When I got the result of my test, it showed that only 5 other people have tested positive for this mutation, so I'm guessing the significance of it won't be known anytime soon.

in_cognito

Thanks for your replies ladies!

I do plan on seeing a genetic counselor once I receive all the paperwork in the mail.  Should I consider myself BRCA positive or negative?  Although it says unknown clinical significance - it seems to be a significance to me since I got breast cancer, right???? And there is a mutation?  I guess this is something a genetic counselor can clarify as well.

GC1

At this point, you can't necessarily consider yourself positive or negative.  A variant can either go one of two ways, it could be a cancer-predisposing mutation or it could be a harmless change.  Although you have had breast cancer, that doesn't necessarily mean that it is of significance. There are many women who have breast cancer and have a strong family history who don't have mutations in these genes.

What it leaves you with is a lot of uncertainty at this point.  In some cases medical recommendations are based on family history when a woman is found to have a variant.  It is also important to look at your family history in order to determine how significant this variant may be.   

Mutd

The boilerplate advice is always the same. If you have a variant of uncertain significance, you are neither positive nor negative, don't even use the test result for anything important.

 In practice "uncertain" doesn't mean "completely in the dark". Some uncertains are really absolutely unknown. But others give some clues, like how important was a particular location in the gene, how dramatic was a change, how the variant was inherited in the families etc. In practice, most variants lean toward being benign. Some lean towards the danger zone.Some yield stronger hints and others don't have much info yet.

What's common between all the "uncertains" is, well, that none of them rises to the threshold of certainty. One can't like go before a judge and say that yes, absolutely, beyond all reasonable doubt, this variant is "good" or "bad". But the "preponderance of evidence" may be strongly leaning one way or another already. But how one can use this sort of an incomplete proof, that's a complicated question.

in_cognito

GC and Mutd - thanks for the replies.  I remember my doctor mentioning something about having my parents blood drawn - I will have to get the paperwork in the mail and read over it all - I was in a foggy state of mind.  I wish the results of my test were concrete so it could drive my decision to do a bil mx as well as having my ovaries removed.  I want to be as aggressive as possible since I have a 2 year old and 8 week old baby.  All the BC in my family seems to be on my father's side.  I have 2 aunts that were >50 when diagnosed and a cousin diagnosed at 49.  Just more things to ponder. 

Mutd

in_cognito, there may be more stuff to Google in the lab report. The exact name of the mutation may be very useful sometimes. Of course you've made you mind about the prevention plan anyway, so maybe you don't really need this extra piece of mind like knowing more about your specific variant, but still...

The free family testing is usually offered to both parents and to all relatives with cancers, to find out if the variant follows the same branches of the family tree as does the risk of cancer. Of course it is a double edged sword because as more people in the family get tested, more of them recieve, well, uncertain results. Free results, yes, but not immediately useful.  The point is that every added family test moves the variant a step closer to "certain" classification. Once the critical mass of information is collected, then all of these lab results will become "certain", and not just for your immediate family but also for all your distant "genetic kin" (others who grapple with the same variant). So it's kind of, part getting a not-too-useful freebie which will become useful in the future, part helping the community.

kittycat

My mom won't get tested.  I think she's afraid it will be "her fault" that my sister and I have the gene.  My father had bone marrow cancer, but didn't know (we got his diagnosis the day after he passed away).  He died of pneumonia.  My mom and aunt believe that it came from my dad, since cancer is so rampant on his side.  However, their half sister had breast and ovarian cancer.  So, you never know.  And both my mom and aunt had hysterectomies at an early age, so their risks were reduced. 

Mutd

So many parents wouldn't get tested. It is a fact of life. Forget these intractable uncertain variants ... even the known mutations split the families too often, who doesn't want testing and who doesn't even want any information, who feels guilty and who blames the others. As if there is any real guilt in the randomness of the chromosomes!

 And you are absolutely right, Kittycat, in many families, just like in yours, the genetic riddle is too complex to solve it with just a test of a parent. "Some cancer on both sides" and "the older generation is free of cancer but they had hysterectomies" are two of the most common difficulties in interpreting the results of a family testing. 

Of course if the variant in your family was uncertain and you were out to investigate it... If it was on you father's side ... and if additional tests detected it in his relatives with cancer ... then the pattern would become stronger. But if for example it was from your mother, then the search for clues might just deadend?

This is always the case in genetics. Some family trees just beg to be studied, and others look pretty undecipherable.

JennyB100104

Mutd, Yes, that's exactly the way I'm looking at my mutation of uncertain significance. Not positive or negative, just non-information. (Even though it makes me a little crazy to do that!) I'm hoping to get my parents in to get tested, but they're...well, it's so complicated for them, they might not do it. I'm going to try to drag my dad into my oncologist when he's visiting me in two weeks! 

One of my friends said she was offered a bilateral mastectomy & ooph when her doctor found out about her mutation of uncertain significance. Her mother had early-stage bc, but she and her siblings have had no history of cancer. I didn't get that at all--thought it was a little bit overkill. 

in_cognito

Well, I spoke to a genetic counselor, I wrote an email to Dr. Susan Love's website and I spoke with someone at Myriad.  They all told me that basically there is a mutation on the BRCA gene, but it really doesn't mean anything other than there is a mutation and they think it is mostly due to environmental causes.  All three parties said that I should not consider myself positive by any means, even though I do have breast cancer.  I asked about the significance of having my parents tested and they all said that if one of my parents test positive for the same gene mutation, we would know that they passed it onto me, or it was just from whatever weird reason.   If I did get the mutation from either side, they said it still is of no significance, other than to have this information in their research database.  So, still a whole lot of nothing other than not to count myself positive at this point. 

in_cognito

Well, I spoke to a genetic counselor, I wrote an email to Dr. Susan Love's website and I spoke with someone at Myriad.  They all told me that basically there is a mutation on the BRCA gene, but it really doesn't mean anything other than there is a mutation and they think it is mostly due to environmental causes.  All three parties said that I should not consider myself positive by any means, even though I do have breast cancer.  I asked about the significance of having my parents tested and they all said that if one of my parents test positive for the same gene mutation, we would know that they passed it onto me, or it was just from whatever weird reason.   If I did get the mutation from either side, they said it still is of no significance, other than to have this information in their research database.  So, still a whole lot of nothing other than not to count myself positive at this point. 

DanielleSurvivorSince03-09

It's been a few months since these posts but I also have a BRCA1 mutation of uncertain significance and wondering if any of us have the same one.  My report says "D936E (2927T>G)".  Anyone have that same mutation?

Karen3

Hi all

I had the genetic testing after being diagnosed as triple negative BC last September at the age of 46. Mum had Ovarian Cancer at the age of 49, my maternal Aunt had Breast Cancer and my Maternal Uncle died of Pancreatic Cancer last year at the age of 62.My Breast Cancer proved to be resistant to chemotherapy (my chemo treatment was withdrawn half way through) and my Oncologist said this was not unusual when a gene mutation was involved. 

I got my BRCA results on Christmas Eve to say that they found a 'variant of unknown significance in BRCA1'. I was told that research is ongoing in to the BRCA gene mutations and I was asked to take part in the BRCA 3 research in the UK. I along with members of my family affected by cancer, have been asked to give a blood sample.

So, you are not alone! For my part, taking part in the research has been an important part of moving forward with this. Lets hope that one day, they will have a critical mass of evidence to declare a new BRCA gene mutation.

Karen x

Mutd

Danielle, your D396E must be quite rare, because there isn't a word about it on the Internet. But it doesn't look like a dangerous change. In the protein code, letters "D" and "E" stand for two very similar "construction blocks". Very similar and therefore interchangeable in many cases. And in this case, Mother Nature easily interchanges the letters at BRCA1 position 396. Many animals, from mouse to elephant, have "E" instead of "D" at this position, so most likely it causes no harm to us humans too.

 Karen, what about your specific mutation? Do you know its name? Did the lab describe it as "an absolute unknown"? Or as a mutation with some emerging hints about its possible significance?

DanielleSurvivorSince03-09

Mutd, thanks so much for that information!  I makes me feel so much better.  How do you know all that?  I couldn't find anything on the internet but I guess I was searching the right things. 

Karen, I'm so sorry to hear about all the breast cancer in your family.  I hope your genetic study goes well.

Karen3

Hi Mutd

I was just told that I had a 'mutation of unknown significance in the BRCA 1 test'. I did ask the Oncologist to provide further detials as my niece has a doctorate in bio medical sciences and she wanted to know more. But I was told that was the only info provided to the Oncology team by the labs. They did say that in their opinion there was a genetic predisposition given the clustering of cancer on the maternal side of the family. Hence, the invitation to take part in the studies in the UK. I wish I knew more details to pass on to you......I see the Oncologist again in January 2012 (seems ages away!) so I will definately ask again if they can provide more info.

 Karen XX.

Mutd

Karen, it's always a good idea to get copies of your most important lab test reports, and even more so for the genetic tests. The physicians may misread the results (we hear about so many examples of this in the cancer forums!). Or their interpretation may be outdated (especially for the genetic tests which are still new to them, and indeed the genetic knowledge keeps accumulating so fast!). But most importantly, because there is more cancer clustering in your family, and the relatives will need to "compare notes" to make their decisions.

Another  extremely important thing to do is to get help from a genetic counselor. It's always a good idea for any BRCA test result, but the "uncertain" results really stand out. There is absolutely no question that these hard cases require a discussion with a good GC!

Danielle - the D936E story and what you can find online about other bilogical species ... yes you can find everything online, but it's quite a bit more complicated than a simple Google search. A GC should have no problem searching for similarities with a specific mutation in other organisms, but it still takes time and effort. I don't know if anybody can provide a better "cookbook recipee" for such a search ... here is a rough draft.

First you need to find the normal protein code in the human species. Find National Center for Bioinformatics (NCBI) Protein database http://www.ncbi.nlm.nih.gov/protein. Search for your gene (for example, "BRCA1 human"). You get a database page (http://www.ncbi.nlm.nih.gov/protein/AAC37594.1) with a desription of the protein, followed by the entire protein code.

Then you need to "change spelling" to match your mutation. Copy 40-50 letters of the protein sequence around position 936 (in your case), paste into a word processor, replace the "d" by "e". Now you get a partial fragment of your own variant protein spelled out. Time to compare with the rest of the NCBI database.

At the top of the right panel of the protein page, there are links under the heading "Analyze this sequence". The first link says, "Run Blast". That's the one to use. Click, paste you "edited sentence", and start the search which may take a few minutes. After it's done, you will see the entire list of similar proteins. Keep scrolling down and take notes which of the "similar sequences" has the E in the right spot, and which ones have the D. Sounds simple but ... 

DanielleSurvivorSince03-09

Thanks Mutd.  I'm at the site you mentioned and think I followed the instructions correctly.  Should I just replace "d" with "e" or the other way around too (replace "e" with "d")?  Also, I typed in my replaced string and Ran Blast - what does this tell me?  There is a bunch of information I'm not sure which "accession" I should be looking at.  Do you by any chance work at Myriad and that's how you know all this?  Thanks for your help!

Mutd

Thanks for trying, as usually it's hard to cook a difficult dish with a short recipee from the Internet :)And this search is very hard to do with NCBI "Blast" ... much harder than I thought.

Trying to fill in more details now: so the page to start is

http://www.ncbi.nlm.nih.gov/protein/AAC37594.1 

 Around "position 936", the protein sequence reads like this:

feceqkeenq gknesnikpv qtvnitagfp vvgqkdkpvd nakcsikggs rfclssqfrg 

I put "letter #936" in boldface, it is a "d" of course (the "normal" letter). Now let's put an "E" in its place:

feceqkeenq gknesnikpv qtvnitagfp vvgqkekpvd nakcsikggs rfclssqfrg

Tha's how your personal version of the protein looks like. Time to "run blast"! (NCBI website suggest that you run the whole code AAC37594, but we delete it and paste our little edited sentence instead. Because it's kind of pointless to search for all similar things in the world, we just need to see what may be similar to your variant)

So the search runs its course, and then you scroll down to :alignments" (yourcode and the similar genes from the database, lined up alongside with one another). First thing you see is the comparison with normal human code:

FECEQKEENQGKNESNIKPVQTVNITAGFPVVGQKEKPVDNAKCSIKGGSRFCLSSQFRG FECEQKEENQGKNESNIKPVQTVNITAGFPVVGQK+KPVDNAKCSIKGGSRFCLSSQFRG

The letters are exactly the same except for your "E" where the plus sign means that the two letters are similar but not the same. I thought you could keep scrolling down until you find something without the annoying "plus sign", but the NCBI blast must be getting bored after a hundred results But if I look one species at a time ... for example "elephas", that's the scientific name for you know what ... then you get one of your "personal matches in the animal kingdom":

CEQKEENQGKNESNIKPVQTVNITAGFPVVGQKEKPVDNAKCSIKGGSRFCLSSQFRG
C +KEENQG E IK Q V++ AG+P QKEKP D K SIKG S C SSQFRG

How to be sure that you found all of the matches without more specialized software ... I don't know, I'm stumped

DanielleSurvivorSince03-09

Wow thanks for your help!  They did tell me when I had the test done that I'm one of only four people with the same mutation.  Thanks for all your help!  I'm comforted just knowing you said it was probably nothing to worry about being d/e. 

MRDRN

I will add that there is a good reference here:

http://www.breastcancer.org/news_research/ask_expert/06_2010/q3.jsp   I am surprised that my BC was notTN but glad and feel relieved to have done the Bi Mx.

BanR

hello all..

is this thread still active...

its more than 3 years since you all interacted over this and here i come with the same query! tried following the links by Mutd, but i could find out how..it looks complicated.

I am got this report...3 mutations in brac2 detected, 2 have no clinical relevance and 1 has unknown clinical relevance.

chemo going on for triple negative cancer diagnosed 3 months ago.

i am 35.

Mutd

BanR I couldn't make sense of this "g17113A>C" mutation name. Could you check spelling / also check if additional names are listed? Sometimes labs use the "g-number" system of calling genetic variants. The lowercase "g" stands for "genomic position" and the numbers are counted all the way from the beginning of a chromosome (and so the numbers may be astronomical ... because an average chromosome is so long, it has more than 100 million positions). The usual range of g-numbers for the BRCA2 gene is somewhere between 32 and 33 millions... so this 17 thousand and a change number just doesn't look right.

BanR

Sure... will check in a while and repost the number again.

BanR

Hi..checked it. Its the same

a homozygous polymorphism ,g.17113A>C that results in an amino acid substitution, the clinical significance for which is not yet established.

is what is written.

Mutd

a homozygous polymorphism ,g.17113A>C that results in an amino acid substitution

and they didn't mention that the substitution is at the amino acid position 372, did they? I would reserve a few choice swearwords for the lab which ran your test. It looks like they used an obsolete map and a nonstandard nomenclature (system of names and numbers). How could a genetic counselor advice you if the name of the variant is so tangled that it's almost impossible to recognize?

It is confusing but AFAIK in the modern HGVS nomenclature, this polymorphism would be called c.1114A>C. This c.1114A>C polymorphism isn't some rare mutation. Quite the opposite, it is extremely common. The majority of people have it. In fact about 25% of European / Caucasian women are also homozygous (meaning that they inherited one copy from the mother and one from the father). Of course most genetic labs conclude that it is quite benign ... but perhaps a lab with a confusing naming system just might have never figured it all out?

BanR

yes yes..there is a name for the amino acid substitution . it goes like this ..... p.Asn372His. You have a very good knowledge of genetics! I checked again..its g.17113A>C. 

They found 2 other mutations too but both of no clinical relevance. Only the one mentioned above is a mutation of unknown significance

I guess I should get it rechecked then, will discuss this with my counselor.

also i hear that there is a new gene called brca3 and studies are going on. if not brca1 or brca2, it could be some other undiscovered gene else how on earth could some one in her mid thirties like me, get cancer.  I understand there are a few risk factors which puts a young woman at risk like, family history, early age of menarche, alcohol, having children very late, not breastfeeding them enough, taking hormonal pills, lack of excercise, obesity etc etc. I seem to have none of these ( except a very distant relative getting ovarian cancer at young age)

Mutd

BRCA3 is more like a metaphor, not like an actual gene. It used to be the Holy Grail of the familial breast cancer research, but the name turned out to be a misnomer because it's become clear to the geneticists that there is no 3rd gene which would be as important and as dangerous as BRCA1 and BRCA2. Instead, there are additional high-risk genes but their mutations are very rare. There are also genes with more common mutations but their risk levels are nowhere near as high as BRCA1/2.

When Mary-Claire King hunted for "BRCA3" in high-risk "mystery gene families", her lab mostly found a difficult-to-detect class of mutations in BRCA1 instead, called large rearrangements. An old gene but a new (at the time) type of mutations. Did your testing lab search for large rearrangements in the BRCA genes? It's becoming a more or less standard practice but still, not all the labs do it...

(Oh, and p.Asn372His a.k.a. N372H... occasionally, labs which do not specialize in hereditary cancer used to report it as uncertain-significance, at first because of a very old Chinese publication which suggested a correlation between this variant and some kind of a gastro-intestinal cancer in Chinese males ... but their report might have been a statistical fluke and never really panned out. Still there was occasional speculation about a possibility of a minor increase in breast cancer risk in the carriers of N372H, but it's been pretty much put to rest a decade ago. See D.G. Cox, S.E. Hankinson and D.J. Hunter, "No association between BRCA2 N372H and breast cancer risk", Cancer Epidemiol Biomarkers Prev 14 (2005), 1353-1354)