Here is a roundup of everything I have learned about my own mutation.  If you have this mutation, please contact me!

C61G is also coded as 181T>G.

What does these letters and numbers mean??

Check out BRCA Mutations Made Simple for further background on all these terms.  The first thing to know is that C61G is a missense mutation at nucleotide 181 on the BRCA1 gene.  At that nucleotide I should have a “T” and instead I gave a “G” in my DNA sequence.  That change results in a Cystine being replaced with a Glycine at amino acid 61.  The C in C61G stands for Cystine, and the G stands for Glycine.

The first thing to know is that you can look up our mutation in a database called ClinVar.  Here is the link to our mutation’s page.  This is very important because it shows which labs have reported this mutation as being harmful, and it’s also a starting point to learn some of the nomenclature that scientists use when referring to this mutation.

Here is a picture of the BRCA1 tumor suppressor protein.  The arrow points to the exact spot where my mutation causes a ‘break’ in function on this protein.

 

 

 

Here is a close-up:

 

 

How did I find this?  Well, I had help from a computational biologist* who was kind enough to teach me some things.  Here is what he shared with me:

This webpage is kind of a comprehensive summary of the BRCA gene. Scroll down to find a summary of C61G:
http://www.uniprot.org/uniprot/P38398

That page links to a more detailed page about the mutation itself:
http://web.expasy.org/variant_pages/VAR_007757.html

Some summaries of the structure of the BRCA protein in the region of the mutation are here:
http://www.ebi.ac.uk/pdbe-srv/view/entry/1jm7/summary.html
http://www.rcsb.org/pdb/explore.do?structureId=1jm7

Those pages link to the scientific paper where the structure was published:
http://www.ncbi.nlm.nih.gov/pubmed/11573085?dopt=Abstract

I’ve attached a couple of pictures that I made from the structure. It is important to understand that the BRCA protein has 1863 amino acids in it. There are 22 known structures (3D pictures) of the protein, most of which are of the last 200 amino acids. There is only one known structure of the first part of the protein where your mutation is. That structure covers the first 110 amino acids, so your mutation is found in that structure. That’s the structure in the pictures I’ve attached.

Note that I’ve highlighted your mutation in a green halo with an arrow pointing to it. The C61G mutation means that the highlighted “bent stick” is gone. This means that it isn’t there to connect to the sphere with the purple dashed lines. That sphere is a charged zinc atom (an ion). This binding of a zinc atom by sulfur-containing amino acids (a “cysteine”) is called a “zinc finger”. Usually, a zinc finger has 4 cysteines that bind the zinc. This particular zinc finger has three cysteines and another amino acid called “arginine”. This means that the zinc is not bound quite as strongly. So when you remove one of the three cysteines (as in your mutation), that zinc just kind of falls away. When it falls away, the shape of the protein changes and that change prevents BRCA from binding to BAP1 and doing its job as a tumor suppressor.

Remember, we don’t have the whole picture here; we’re missing the vast majority of the protein structure, so we are missing context. But the reason why your mutation has such a drastic impact is clear from these pictures.

 

*THANK YOU Darrell Hurt, Section Leader at NIH, for helping me to understand my mutation in a new way.  PLEASE NOTE:  Darrell’s is NOT a medical doctor and his input is not to be taken as medical advice.  His views are in no way representative of the NIH.