Teri Smieja is the co-author of the soon to be released book: “Letters to Doctors” (The BRCA and Hereditary Breast and Ovarian Cancer Syndrome Edition; Patients Educating Medical Professionals Through Practical True Life Experiences), co-creator and administrator of the BRCA Sisterhood on Facebook, a former blogger at Teri’s Blip in the Universe and a big fan of Brave Bosom!
A few days ago a biology class broke out in a few BRCA Facebook groups. I was trying to simplify the meaning of a BRCA mutation by breaking down what the mutation means. I used my own as an example (187delAG). That initial post prompted a flurry of discussion from other BRCA mutants who wanted more specifics on their individual mutations. We had lots of:
“Oooh, what’s mine mean?” “Do me next!” “What is an exon?” “What is a nucleotide and how does it affect me if I don’t have one?” “Why do I have an X in my mutation?” “Why do I have numbers after ‘del’ instead of letters like other people?”
A whole lot of BRCA ladies were suddenly excited about understanding DNA in a different way! Me, being a non-science major had to go through a mini-genetics 101 lesson from my very intelligent twenty-one year old son, Steve Cunningham, and his uber brilliant girlfriend Karen Leopold, both about to begin their fourth years at the University of Minnesota, as double majors in biochemistry and GCD (genetics, cell biology, and development) with minors in computer science. Thanks to them, I was able to understand enough of this genetic, scientific, big worded biology stuff to try to translate into normal-people-speak, for the rest of us.
The initial scientific frenzy inducing note that I posted on facebook is here:
A Simple Explanation of Mutations
My mutation is 187delAG. I already knew that referred to the area within my DNA that was missing information, but I didn’t fully understand what that location meant.
Here is a simplified explanation of a BRCA mutation (some info has been omitted/glossed over for ease of explanation):
So, just say that the BRCA1 DNA contains roughly 6000 nucleotides (nucleotides are the building blocks within our DNA).
So picture a long line of numbers from 1 to 6000. 187delAG means that I’m missing the AG nucleotides 187 steps into the BRCA DNA.
If you have a BRCA mutation, that means that the sequence is wrong, with an extra letter (INS), missing letters (DEL) or switched letters.
All of the DNA after an insertion or deletion is read as nonsense (this is what frameshift refers to) because after 187 it’s all based on misread information.
DNA is read in sets of 3.
A ‘normal’ sequence would be something like:
123 123 123 123 123 123
But a mutation could look like:
For an INS (or insertion):
123 123 122 312 312 312 3
Those with a C insertion have ONE extra nucleotide – if a ‘normal’ person has 6000 nucleotides, then they’d have 1 more than that – at 6001
For a DEL (deletion):
123 123 131 231 231 23
Those with an AG deletion are missing TWO nucleotides – if a ‘normal’ person has 6000 nucleotides, then I’d have 2 less than that – at 5998
123 123 133 123 123 123
Someone with a ‘switch’ mutation has the correct amount of nucleotides, but one of the numbers is switched.
Karen drew this awesome and sort of easy to understand diagram for us, which helped us to better understand WHAT it means to have a BRCA mutation:
Why does all or any of this matter?
Well, it matters because understanding this aspect of DNA will help us to understand our own, individual mutations and what they may mean to us. When we learn that we have a BRCA mutation we are put in a situation of choosing a ‘solution’ from about five current ‘solutions’ available to us now:
- Bury our head in the sand and hope it’ll go away.
- Increase our surveillance.
- Have risk reducing surgeries.
- Go on a chemo-prevention drug that can cause uterine cancer if you stay on it for longer than five years.
- Change your lifestyle and hope for the best.
As we’ve so few choices, and let’s face it the choices we do have pretty much suck, many of us want to make the most informed decision possible. Understanding what it really mean to have a BRCA mutation can help us with making the best choice that we can. And knowing this information is a step towards fighting for better options.
Here is a breakdown of just a few of the mutations we spoke of on facebook, as explained by Karen Leopold or myself :
Some mutations – or ‘variants’ – are completely harmless. There could be changes in your DNA that show up on a genetic test that actually don’t increase your risk of cancer. This is why genetic counseling is so important!! There are also variants where we don’t yet have enough data to know whether the change in your DNA is harmful or benign. Before making any big decisions about risk reducing surgeries, make sure you talk to a certified genetic counselor who has training to interpret your results. Unfortunately primary care doctors, oncologists, breast surgeons, and plastic surgeons do not have the right training to know whether or not your variant is harmful. You don’t want to make a big mistake by moving forward with surgery without consulting with the right experts!!
‘Deletions’ make the rest of a protein unable to function. For example, if you have the mutation 8765delAG (BRCA2) you are missing the A (adenine) & G (guanine) on the 8765 area of your DNA… the rest of the protein beyond that missing A and G become nonsense when your body tries to create a working protein
A good way to think of it is this: You have an instruction manual for making a car (the instruction manual represents the DNA). The car represents the protein. The instructions for making the engine (the most important part of the car) might be on the last page – say page 9663 – of the instruction manual (this could translate to a mutation BRCA2 9663delGT). If that part of the manual is deleted, then the engine will never be made and the car will never run. Thus, a deletion on the last page of the manual could be just as harmful as an earlier mutation (say, one that ruined the rest of the manual, or one that deleted instructions for the wheels).
Mutations can happen anywhere on a gene. Here’s another example. If you have the mutation of c.3331_3334delCAAG it means you are missing a C two A’s and a G between the 3331 and 3334 area of your DNA.
An important part of the BRCA gene (like instructions for the engine), was probably deleted, causing the protein not to work. A meaningful code CAN be located anywhere along the gene. However, if you have an insertion or deletion early on (and you insert or delete a number of nucleotides that is NOT a multiple of 3), then the rest of the protein (including later meaningful parts of the code) will become rubbish. This is because the “reading frame” gets shifted, and it is called a “frameshift mutation”. This is not to say that a later mutation isn’t harmful, but an early insertion/deletion will effectively cause ALL later locations to be misread as well (this has to do with the reading frame as described in the diagram).
Do you have mutation 6174delT? It means that you have one nucleotide (a thymine – denoted as “T”) missing at nucleotide number 6174 (about midway through the BRCA2 gene). This is a frameshift mutation.
Some of us have ‘Switch’ mutations. A ‘switch’ mutation, for example, is IVS 5-11T>G: IVS. This means the mutation is in an intron. Usually, mutations in introns are safer than mutations in exons, HOWEVER, there can still be harmful (in your report it may say “deleterious”) mutations in introns that can be harmful. T>G means that a Thymine (T) got changed to a Guanine (G). 5- 11 means that this change (this mutation) happened 11 nucleotides from the end of intron #5.
Some of us have ‘Exon’ Mutations. Mutations can happen anywhere on a gene. Here’s another example. If you have the mutation of c.3331_3334delCAAG it means you are missing a C two A’s and a G between the 3331 and 3334 area of your DNA. Mutation R3128X, on exon 25 with no A, C, G, T, del or ins means that on exon 25 of her DNA, there was a mutation. This mutation in the BRCA DNA caused the resulting BRCA protein (which is encoded by the BRCA DNA) to be mutated at amino acid (AKA protein building block) number 3128. Where there was supposed to be an R (Amino acid Arginine) in the protein at this location, there is now a “stop codon” – denoted by X – at that place. A stop codon means that none of the protein after that point is made, so this change completely breaks the protein. (Just for background – know that while the DNA code only contains 4 letters, the protein code contains 20).
This should hopefully give ya’ll an idea of how to understand what YOUR mutation means. Karen and Steve are still on their summer break so have a little time to respond to your specific questions. For ease of keeping everything in one place, please put your comments directly on this blog.
Oh, and feel free to share this blog with your networks. Thanks so much!
BTW, it’s still important to let you know that you shouldn’t base any big, important medical decisions off our interpretation of your mutation. You’ll still want to confer with practicing doctors and genetic counselors when making any big decisions.
Any questions? Comments? Thoughts?
Follow my blog with Bloglovin