ClinVar Miner

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

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Total submissions: 13
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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 The p.C39Y pathogenic mutation (also known as c.116G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 116. The cysteine at codon 39 is replaced by tyrosine, an amino acid with highly dissimilar properties. The cysteine at codon 39 is a putative zinc-binding residue occurring in the functionally important RING domain of the BRCA1 protein. Cells with p.C39Y are deficient in the control of centrosome number (Kais Z et al. Oncogene. 2012 Feb 9;31(6):799-804). Other studies have demonstrated abolishment and decreased activity of ubiquitin protein ligase function the BRCA1 RING finger in vitro (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). In addition, p.C39Y failed to reverse gamma radiation (IR) hypersensitivity in vivo (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9). Furthermore, cells with p.C39Y were found to be defective in the repair of double-strand breaks by homology-directed recombination (HDR) and double-strand break repair by the single-strand annealing (SSA) pathway (Towler WI et al. Hum Mutat. 2013 Mar;34(3):439-45). Other studies found cells with p.C39Y to be deficient in BARD1 binding (Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). The results from a small colony phenotype assay, which monitors the BRCA1-dependent growth of yeast colonies, also suggested p.C39Y is deleterious (Millot GA et al. Hum Mutat. 2011 Dec;32(12):1470-80). In addition to these functional studies, this mutation has been identified in multiple breast and/or ovarian cancer families to date (Stegel V et al. BMC Med Genet. 2011 Jan 14;12:9; Juwle A et al. Med Oncol. 2012 Dec;29(5):3272-81; Santarosa M et al. Int J Cancer. 1998 Nov 23;78(5):581-6). Furthermore, a different alteration at the same codon, p.C39R, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 Health, Inc RCV000222558 SCV000688318 pathogenic Hereditary cancer-predisposing syndrome 2020-09-14 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tyrosine at codon 39 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in significantly reduced DNA repair activity, defective cell proliferation in haploid cells, defective E3-ubiquitin ligase activity, and impaired/reduced BARD1 binding, (PMID: 11320250, 20103620, 25823446, 27272900, 30209399). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 9808526, 15340362, 22752604, 23397983). This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
3DMed Clinical Laboratory Inc RCV000677804 SCV000803963 pathogenic Breast neoplasm 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
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000030973 SCV001499754 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Invitae RCV000496391 SCV001583684 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 39 of the BRCA1 protein (p.Cys39Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 9808526, 22923021, 21232165, 22752604, 26852130, 23397983). This variant is also known as 235G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37392). This variant affects the highly conserved Cys39 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421). Experimental studies have shown that this missense change impacts BRCA1 function as assessed by multiple different assays, including ubiquitin ligase activity, BARD1 binding, homology directed recombination, single-strand annealing, and centrosome amplification (PMID: 20103620, 21725363, 21922593, 23161852, 11320250, 27272900). Different missense substitutions at this codon (p.Cys39Ser, p.Cys39Gly, p.Cys39Arg) have been determined to be pathogenic (PMID: 23683081, 19504351, 18500671, 21990134, 12827452, 19543972). This suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235619 SCV001553534 pathogenic not provided no assertion criteria provided clinical testing

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