ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.116G>A (p.Cys39Tyr) (rs80357498)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222558 SCV000277193 pathogenic Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification;Well-characterized mutation at same position
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.
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
Color RCV000222558 SCV000688318 pathogenic Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677804 SCV000803963 pathogenic Neoplasm of the breast 2017-08-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235619 SCV001249218 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030973 SCV000053564 pathogenic Breast-ovarian cancer, familial 1 2006-12-11 no assertion criteria provided 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
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
Brotman Baty Institute,University of Washington RCV000030973 SCV001241902 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.