User:Jaime.Prilusky/Test/Stats

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== Commentary==
== Commentary==
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This mutation Cys61Gly disrupts zinc ion binding necessary for stability of the RING structure <ref>pmid 22172724</ref><ref>pmid 16403807</ref>. As a consequence, it abolishes interaction with BARD1 and also with E2 conjugate enzymes and thereby reduces its ubiquitin ligase activity. BRCA1 C61G homozygous mice leads to embryonic lethality due to loss of BRCA1 RING function. Drost et al <ref>pmid: 22172724</ref> showed that residual activity of this C61G mutant BRCA1 protein with a dysfunctional RING domain triggers acquired resistance to PARP inhibitors and platinum drugs. For these tumors DNA repair process is partially intact, although homologous recombination (HR) reporter activity is very low. According to Sweet et al <ref>pmid: 19543972</ref>, the odds of pathogenicity of this mutation is 5E+05:1, in favor of being deleterious.
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This mutation Cys61Gly disrupts zinc ion binding necessary for stability of the RING structure <ref name='p22172724'>pmid 22172724</ref><ref name='p16403807'>pmid 16403807</ref>. As a consequence, it abolishes interaction with BARD1 and also with E2 conjugate enzymes and thereby reduces its ubiquitin ligase activity. BRCA1 C61G homozygous mice leads to embryonic lethality due to loss of BRCA1 RING function. Drost et al <ref name='p22172724'/> showed that residual activity of this C61G mutant BRCA1 protein with a dysfunctional RING domain triggers acquired resistance to PARP inhibitors and platinum drugs. For these tumors DNA repair process is partially intact, although homologous recombination (HR) reporter activity is very low. According to Sweet et al <ref>pmid: 19543972</ref>, the odds of pathogenicity of this mutation is 5E+05:1, in favor of being deleterious.
==Experimental results==
==Experimental results==
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Heterozygous mutation facilitates tumor development and homozygous mutation is embryonically lethal in a mouse model where p53 is targeted deleted in the mammary gland and BRCA1 deletion is varied according to the required zygosity <ref>pmid 22172724</ref>. High impact in yeast two-hybrid assay <ref>pmid 16403807</ref>.
+
Heterozygous mutation facilitates tumor development and homozygous mutation is embryonically lethal in a mouse model where p53 is targeted deleted in the mammary gland and BRCA1 deletion is varied according to the required zygosity <ref>pmid 22172724</ref>. High impact in yeast two-hybrid assay <ref name='p16403807'/></ref>.
==Impacted biological activities==
==Impacted biological activities==

Revision as of 10:47, 4 November 2018

Contents

Classification

BRCA Exchange: Pathogenic, ClinVar: Pathogenic

Commentary

This mutation Cys61Gly disrupts zinc ion binding necessary for stability of the RING structure [1][2]. As a consequence, it abolishes interaction with BARD1 and also with E2 conjugate enzymes and thereby reduces its ubiquitin ligase activity. BRCA1 C61G homozygous mice leads to embryonic lethality due to loss of BRCA1 RING function. Drost et al [1] showed that residual activity of this C61G mutant BRCA1 protein with a dysfunctional RING domain triggers acquired resistance to PARP inhibitors and platinum drugs. For these tumors DNA repair process is partially intact, although homologous recombination (HR) reporter activity is very low. According to Sweet et al [3], the odds of pathogenicity of this mutation is 5E+05:1, in favor of being deleterious.

Experimental results

Heterozygous mutation facilitates tumor development and homozygous mutation is embryonically lethal in a mouse model where p53 is targeted deleted in the mammary gland and BRCA1 deletion is varied according to the required zygosity [4]. High impact in yeast two-hybrid assay [2]</ref>.

Impacted biological activities

E3 Ubiquitin ligase activity Homologous recombination

Variant

C61G, chr17:g.41258504:A>C, NP_009225.1:p.(Cys61Gly), rs28897672

Allele Frequency

2.825e-05 (ExAC minus TCGA)


References

  1. ↑ 1.0 1.1 Drost R, Bouwman P, Rottenberg S, Boon U, Schut E, Klarenbeek S, Klijn C, van der Heijden I, van der Gulden H, Wientjens E, Pieterse M, Catteau A, Green P, Solomon E, Morris JR, Jonkers J. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell. 2011 Dec 13;20(6):797-809. doi: 10.1016/j.ccr.2011.11.014. PMID:22172724 doi:http://dx.doi.org/10.1016/j.ccr.2011.11.014
  2. ↑ 2.0 2.1 Morris JR, Pangon L, Boutell C, Katagiri T, Keep NH, Solomon E. Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility. Hum Mol Genet. 2006 Feb 15;15(4):599-606. doi: 10.1093/hmg/ddi476. Epub 2006 Jan , 10. PMID:16403807 doi:http://dx.doi.org/10.1093/hmg/ddi476
  3. ↑ Sweet K, Senter L, Pilarski R, Wei L, Toland AE. Characterization of BRCA1 ring finger variants of uncertain significance. Breast Cancer Res Treat. 2010 Feb;119(3):737-43. doi: 10.1007/s10549-009-0438-6. , Epub 2009 Jun 20. PMID:19543972 doi:http://dx.doi.org/10.1007/s10549-009-0438-6
  4. ↑ Drost R, Bouwman P, Rottenberg S, Boon U, Schut E, Klarenbeek S, Klijn C, van der Heijden I, van der Gulden H, Wientjens E, Pieterse M, Catteau A, Green P, Solomon E, Morris JR, Jonkers J. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell. 2011 Dec 13;20(6):797-809. doi: 10.1016/j.ccr.2011.11.014. PMID:22172724 doi:http://dx.doi.org/10.1016/j.ccr.2011.11.014

Proteopedia Page Contributors and Editors (what is this?)

Jaime Prilusky, Joel L. Sussman

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