Anyone else have a gene mutation but NO family history?

jamer3108

I recently underwent genetic testing to see if I carried the Lynch Sydrome genetic mutation (aunt died of colon cancer at 40). When they tested for that, they did a whole panel of other genes as well. I did not have the Lynch Syndrome mutation, but I do have a mutation in the NBN gene, which makes my risk for breast cancer 30%. The strange thing is, there is NO family history of breast cancer on either side of my family. Also, I guess this mutation is commonly seen in people of Slavic descent, and I'm Irish/German. My doctors all keep saying what a strange case this is.

Is anyone else in the same boat as far as family history goes?

Moderators

Hi,

Just thought that perhaps reading this could be helpful:

http://www.breastcancer.org/risk/factors/genetics

We are thinking of you,

The Mods

cymom

The German side could explain the source of the mutation. I've done a lot of reading on mutations in Eastern Europe for my family. I found this.

http://jay.up.poznan.pl/JAG/pdfy/2010_Volume_51/2010_Volume_51_2--.pdf

I would ask the doctors about how meaningful that 30% number is. How good is the model? How much data is there on this mutation? I understand that doctors can make meaningful predictions about cancer risk for high penetrance mutations like BRCA1 and BRCA2, but with low to moderate penetrance mutations like this, who knows what it means...

DiveCat

Lots of gene mutations still have not been well researched, and do not have clinically actionable guidelines. Those that do are rather limited (BRCA1 & 2, CHEK2, PTEN, etc). There really are only 6 or so that have clinical guidelines based on research. Many others still fall in that "unknown" category and/or are thought to be of low or moderate penetrance. There is ongoing research in these areas, but it does have a lot of catching up to do to develop the kind of knowledge that there is about BRCA1 & 2. A lot of focus really for many years has been on finding that "BRCA3" which I think they have determined likely is NOT there, but there may be other genetic mutations at play so research has shifted a bit to these "others" in more recent years. Recently the University of Washington also discovered additional BRCA1 & 2 mutations that were NOT picked up in other commercial testing...so yes, this stuff is a bit of a moving target!

This can lead to some difficulties in whether or not to test for these other genes (given the absence of any guidelines for them), and how to interpret any results in terms of risk. Likely, they will look more at your family history at this point in the absence of clinically actionable guidelines, but you should talk to a genetics expert about that. It is also not fully known how other genes one may inherit may reduce the impact of mutations. For example, further research has even indicated some with BRCA1 or BRCA2 mutations may have protective factors from OTHER gene variations...which may explain why in some families with BRCA1/2 mutations there is a low (or seemingly absent) history of cancer. This may also be the case for you.

Further, research at first tends to be limited to certain population groups, but as research goes on they often find similar mutations in other populations, though interestingly those populations may not always show the same related risk of cancer or disease that the previous population did (sometimes due to other protective genes at play, etc).

I do not have a BRCA1/2 mutation, or known mutations in the other clinically actionable genes. I do have several risk variants on various SNPs (FGFR2, PALB2, etc) that are thought to confer a lower-moderate risk but non are clinically actionable on their own. What my genetic counselor(s) and medical providers do is look really at my family history which does show a high risk, and just assume for the time being there are polygenic factors or a yet-undiscovered mutation (whether in BRCA or elsewhere). They don't pay too much attention to the risk variants except to say they might be part of the polygenic factors...and to keep records of them because who knows what future research may tell me about them! Decisions are made based on my family and personal history, rather than my genetic makeup, at this point.

Have you talked to a genetics expert about your result? Do they have any recommendations for you? I don't know why your doctors necessarily find it "strange"....we all have DNA that is subject to all sorts of variations and there is a LOT to be discovered yet!

I would not give much thought as to whether the gene mutation could have come from necessarily...it is pretty clear when you go back far enough in one's genetic history there can be all sorts of genetic backgrounds, or contributions that were not "known" to more recent generations. My ancestry is primarily Northern European (English, Welsh, Irish, Icelandic), but my maternal DNA actually shows the presence of French, German, etc as well. I can trace my tree back a few generations, but not indefinitely, and do not know where these other lines came into play. What I can say is that people still moved around a lot even a few generations back, and not everyone can be certain of the parentage of EVERYONE in their family when you go back.

jamer3108

Thanks for the info, everyone.

I haven't spoken to a genetics counselor, only my OB/GYN who ordered the test, and an oncologist. The oncologist also spoke with the hospital geneticist. Their recommendations for me include an annual MRI and mammogram (alternating every six months). Also, general risk reduction through exercise, healthy eating, etc.

The 30% number is based on data that focuses on Slavic populations, so it is possible that my risk could be lower, but there isn't enough data to support that (yet).

I guess saying the doctor's found it "strange" may have been a poor choice of words on my part. Perhaps "surprising" would be a better way to describe it. It was a surprise in general since my OB/GYN suggested the test based on my family's history of colon cancer - not breast cancer. Then add to that the fact that there's no history of breast cancer, and the non-Slavic heritage... Apparently the hospital geneticist was so intrigued by the case that she's taking it to some fellow researchers to discuss.

Anyway, thanks again!

Mutd

J, the "Slavic mutation" in the NBN gene most emphatically doesn't increase the risk of colon cancer, here is the paper:

http://www.ncbi.nlm.nih.gov/pubmed/19393249

For "strange" / "surprising" findings of genetic analysis, there is even a new word coined for this, "incidentalome" (something found in the genome which is completely not what they were looking for, but still important). The ethicists and the geneticists alike are kind of torn about reporting incidental finds. In some extreme cases (like testing children with developmental disabilities), the consensus seems to be to keep the incidental under wraps. But in familial cancer testing, the consensus is to report everything truly important, even when it isn't the exact cancer syndrome the doctor asked about. That's how you got your own brush with the incidentalome.

Breast cancer risk of 30% or smaller magnitude may be easy to miss in the family history. The mutation might have come from your father, even passing through a succession of males, unnoticed. And even if a few female relatives had it too, there remains a strong chance that neither of them developed cancer (it's still at least 70% chance for a carrier to escape it!). An authorization to have MRIs sounds like you got something positive from your testing experience, even if it wasn't what you planned...,