User:Jaime.Prilusky/Test/Stats
ClassificationClassification
BRCA Exchange: Pathogenic, ClinVar: Pathogenic
CommentaryCommentary
This mutation Cys61Gly disrupts zinc ion binding necessary for stability of the RING structure [pmid: 22172724, 16403807]. 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 [pmid: 22172724] 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 [pmid: 19543972], the odds of pathogenicity of this mutation is 5E+05:1, in favor of being deleterious.
Experimental resultsExperimental 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 [1]. High impact in yeast two-hybrid assay [2].
Impacted biological activitiesImpacted biological activities
E3 Ubiquitin ligase activity Homologous recombination
VariantVariant
C61G, chr17:g.41258504:A>C, NP_009225.1:p.(Cys61Gly), rs28897672
Allele FrequencyAllele Frequency
2.825e-05 (ExAC minus TCGA)
ReferencesReferences
- ↑ 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
- ↑ 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