Mutation:BRCA1: Difference between revisions

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John Moult (talk | contribs)
Mutation
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'''Some interesting mutation examples''':
'''Some interesting examples''':


* [http://proteopedia.org/w/Mutation:BRCA1?res=39&mut=R Cys39Arg]
* [http://proteopedia.org/w/Mutation:BRCA1?res=39&mut=R Cys39Arg]
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* [http://proteopedia.org/w/Mutation:BRCA1?res=1706&mut=A Gly1706Ala]
* [http://proteopedia.org/w/Mutation:BRCA1?res=1706&mut=A Gly1706Ala]


Germline mutations in the BRCA1 tumor suppressor gene often result in a very significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. <ref>PMID: 15133502</ref>


The most common cause of monogenic disease is a single base DNA variant resulting in an amino acid substitution. A set of structural effects, such as reduction in hydrophobic area, overpacking, backbone strain, and loss of electrostatic interactions, is used to represent the impact of single residue mutations on protein stability. The distinction between disease and non-disease variants, strongly supports the hypothesis that loss of protein stability is a major factor contributing to monogenic disease.<ref>pmid 16169011</ref>
 
 
A number of germline mutations in BRCA1 are known to substantially increase a carrier’s risk of breast and ovarian cancer. Human BRCA1 is a large protein and appears to be mostly disordered except for the N terminal RING domain and tandem BRCT domains at the C terminus. Many cancer risk mutations truncate the protein, consistent with low or absent in vivo protein levels. There are also a number of missense mutations in the structured regions. Most of these are too rare for clinical significance to have been established, and inspection of the structural context as well as analysis of sequence conservation may help distinguish those which are pathogenic from the benign ones.
<ref>PMID: 15133502</ref>


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