Mutation:BRCA1: Difference between revisions

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Sequence

⎈ mutations with manual annotation; pathogenic; benign; not yet reviewed;
wild type Show which residues have mutations:
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<StructureSection load='' size='340' side='right' caption='' scene=''>
<StructureSection load='' size='340' side='right' caption='' scene=''>
<pre>
<div id='openPageText'>
BRCA1 all mutations
Total non-coding Truncating missense coding
Pathogenic 1028 16 991 21
Benign 502 410 0 86
Not yet Classified 1755 717 205 653
Not yet Reviewed 5292 3177 750 1011
</pre>
See description of data collection at <ref>doi 10.1016/j.jmb.2005.08.020</ref>


ALICE was beginning to get very tired of sitting by her sister on the bank, and of having nothing to do: once or twice she had peeped into the book her sister was reading, but it had no pictures or conversations in it, "and what is the use of a book," thought Alice,"without pictures or conversations?" So she was considering in her own mind (as well as she could, for the hot day made her feel very sleepy and stupid) whether the pleasure of making a daisy-chain would be worth the trouble of getting up and picking the daisies, when suddenly a White Rabbit with pink eyes ran close by her.There was nothing so _very_ remarkable in that; nor did Alice think it so _very_ much out of the way to hear the Rabbit say to itself, "Oh dear! Oh dear! I shall be too late!" (when she thought it over afterwards, it occurred to her that she ought to have wondered at this,but at the time it all seemed quite natural); but when the Rabbit actually _took a watch out of its waistcoat-pocket_, and looked at it,and then hurried on, Alice started to her feet, for it flashed across her mind that she had never before seen a rabbit with either a waist coat-pocket, or a watch to take out of it, and burning with curiosity, she ran across the field after it, and was just in time to see it pop down a large rabbit-hole under the hedge.In another moment down went Alice after it, never once considering how in the world she was to get out again.The rabbit-hole went straight on like a tunnel for some way, and then dipped suddenly down, so suddenly that Alice had not a moment to think about stopping herself before she found herself falling down what seemed to be a very deep well. <ref>Alice's Adventures in Wonderland by Lewis Carroll</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>
 
Mutations are assigned pathogenic or benign status according to the BRCA exchange (https://brcaexchange.org/)  and Clinvar annotations. Six of the seven BRCA Exchange established pathogenic mutations in the RING domain act by destabilizing its three-dimensional structure. Five (C39R, H41R, C44Y, C44S and C61G) disrupt liganding to a zinc atom. The two zinc atoms are critical to the integrity of the small domain linking the two helices, so that loss of liganding is disruptive. A sixth mutation, T37K, introduces a large, positively charged residue into the interior of the zinc binding domain, causing destabilization both through over-packing and through costly desolvation of the charged epsilon amino group. The seventh mutation, L22S, lies in the interface between the RING domain and the obligatory BARD1 binding partner. That mutation introduces a buried hydroxyl group with no internal hydrogen bonds to compensate for the desolvation cost, and also creates an internal cavity approximately the size of two methyl groups, so weakening the protein-protein interaction.
 
== Authorship ==
Data on these pages are compiled by [[User:Yizhou_Yin|Yizhou Yin]], [[User:Lipika_Ray|Lipika Ray Pal]] and [[User:John_Moult|John Moult]] (IBBR, University of Maryland, USA). The mutation interface is built by [[User:Jaime_Prilusky|Jaime Prilusky]] and [[User:Joel_L._Sussman|Joel Sussman]] (Weizmann Institute, Israel) and [[User:Angel_Herraez|Angel Herráez]] (Universidad de Alcalá, Spain). The work is supported by NIH R01 GM120364.
 
</div>
</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>
[[Category: Mutations]]

Latest revision as of 07:46, 28 June 2019

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. [1]

Mutations are assigned pathogenic or benign status according to the BRCA exchange (https://brcaexchange.org/) and Clinvar annotations. Six of the seven BRCA Exchange established pathogenic mutations in the RING domain act by destabilizing its three-dimensional structure. Five (C39R, H41R, C44Y, C44S and C61G) disrupt liganding to a zinc atom. The two zinc atoms are critical to the integrity of the small domain linking the two helices, so that loss of liganding is disruptive. A sixth mutation, T37K, introduces a large, positively charged residue into the interior of the zinc binding domain, causing destabilization both through over-packing and through costly desolvation of the charged epsilon amino group. The seventh mutation, L22S, lies in the interface between the RING domain and the obligatory BARD1 binding partner. That mutation introduces a buried hydroxyl group with no internal hydrogen bonds to compensate for the desolvation cost, and also creates an internal cavity approximately the size of two methyl groups, so weakening the protein-protein interaction.

Authorship

Data on these pages are compiled by Yizhou Yin, Lipika Ray Pal and John Moult (IBBR, University of Maryland, USA). The mutation interface is built by Jaime Prilusky and Joel Sussman (Weizmann Institute, Israel) and Angel Herráez (Universidad de Alcalá, Spain). The work is supported by NIH R01 GM120364.

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ReferencesReferences

  1. ↑ Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol. 2004 Jun;11(6):512-8. Epub 2004 May 9. PMID:15133502 doi:10.1038/nsmb775
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