ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.116G>A (p.Cys39Tyr) (rs80357498)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677804 SCV000803963 pathogenic Neoplasm of the breast 2017-08-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000222558 SCV000277193 pathogenic Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030973 SCV000144352 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000222558 SCV000688318 pathogenic Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030973 SCV000324974 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000235619 SCV000293476 pathogenic not provided 2016-03-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.116G>A at the cDNA level, p.Cys39Tyr (C39Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). Using alternate nomenclature, this pathogenic variant has been previously published as BRCA1 235G>A. This variant was observed in multiple Hereditary Breast and Ovarian Cancer families and has been described as a pathogenic founder variant from the border regions of Italy and Slovenia (Santarosa 1998, Stegel 2011, Juwle 2012, Novakovic 2012, Krajc 2014, Cini 2016). In addition, multiple functional studies have confirmed the pathogenicity of this variant. BRCA1 Cys39Tyr was abolished ubiquitin ligase activity, failed to restore radiation resistance, failed to promote homology directed repair and demonstrated absence of BARD1 binding (Ruffner 2001, Ransburgh 2010). In addition, this variant abrogated the ability of yeast to induce growth arrest in a small colony phenotype assay, displayed centrosome amplification and exhibited deficient double-strand break repair in a single strand annealing assay (Millot 2011, Kais 2012, Towler 2013). BRCA1 Cys39Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Cys39Tyr occurs at a position that is conserved in mammals and is located in located in the RING domain and in a region known to interact with multiple other proteins (Borg 2010, Paul 2014). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496391 SCV000587014 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000030973 SCV000053564 pathogenic Breast-ovarian cancer, familial 1 2006-12-11 no assertion criteria provided clinical testing

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