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

gnomAD frequency: 0.00003  dbSNP: rs80357498

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222558	SCV000277193	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-26	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). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition to these functional studies, this mutation has been identified in multiple breast and/or ovarian cancer families to date (Santarosa M et al. Int J Cancer. 1998 Nov 23;78(5):581-6; Stegel V et al. BMC Med Genet. 2011 Jan 14;12:9; Juwle A et al. Med Oncol. 2012 Dec;29(5):3272-81; Krajc M et al. Clin Genet, 2014 Jan;85:59-63; Cini G et al. BMC Med Genet, 2016 Feb;17:11; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Bakkach J et al. BMC Cancer, 2020 Sep;20:859). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000235619	SCV000293476	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Observed in multiple Hereditary Breast and Ovarian Cancer families, and has been described as a pathogenic founder variant from regions of Italy and Slovenia (Santarosa 1998, Stegel 2011, Juwle 2012, Novakovic 2012, Krajc 2014, Cini 2016); Published functional studies demonstrate a damaging effect: defective ubiquitin ligase activity, homology directed repair activity, BARD1 binding, double-strand break repair, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Ruffner 2001, Ransburgh 2010, Millot 2011, Kais 2012, Towler 2013, Findlay 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 235G>A; This variant is associated with the following publications: (PMID: 26852130, 21232165, 22923021, 15385441, 20103620, 30733539, 29446198, 21922593, 23161852, 15235020, 21725363, 11320250, 9808526, 22752604, 23397983, 25823446, 27272900, 30209399, 30696104, 30040829, 32719484, 30078507, 24389207, 20104584, 8944023, 33087888)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030973	SCV000324974	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222558	SCV000688318	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	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 reported that this variant impacts BRCA1 function in homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399). This variant has been detected in at least eight individuals affected with breast and/or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9808526, 22752604, 22923021, 26852130, 32894085). Other missense substitutions at this codon to serine, arginine, glycine, phenylalanine and tryptophan also have been reported as disease-causing in ClinVar (variation ID 37393, 54151, 54152, 54153, 267497, 867499). 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 Center for Human Genetics 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, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496391	SCV001583684	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 39 of the BRCA1 protein (p.Cys39Tyr). This variant is present in population databases (rs80357498, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9808526, 21232165, 22752604, 22923021, 23397983, 26852130). This variant is also known as 235G>A. ClinVar contains an entry for this variant (Variation ID: 37392). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11320250, 20103620, 21725363, 21922593, 23161852, 27272900). This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12827452, 18500671, 19504351, 19543972, 21990134, 23683081). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000222558	SCV002538002	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000030973	SCV002762791	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-09	criteria provided, single submitter	research	PS3, PS4_STR, PM2_SUP, PM5
Baylor Genetics	RCV000030973	SCV004215094	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235619	SCV004222551	pathogenic	not provided	2022-12-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31396 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 9808526 (1998), 22923021 (2012), 23397983 (2014), 26852130 (2016), 30078507 (2018), 29446198 (2018), and 32772980 (2020). Functional studies report a reduction of E3 ubiquitin ligase activity, RING domain binding, resistance to ionizing radiation, and DNA repair ability (PMIDs: 11320250 (2001), 20103620 (2010), 25823446 (2015), and 33087888 (2021)). Additionally, the variant is linked to the amplification of centromeres, leading to an increase in abnormal chromosomes within cells (PMID: 21725363 (2012)). Yeast assays further support the variant's pathogenicity via colony growth patterns (PMID: 21922593 (2011). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000030973	SCV004823700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-02	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 reported that this variant impacts BRCA1 function in homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399). This variant has been detected in at least eight individuals affected with breast and/or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9808526, 22752604, 22923021, 26852130, 32894085). Other missense substitutions at this codon to serine, arginine, glycine, phenylalanine and tryptophan also have been reported as disease-causing in ClinVar (variation ID 37393, 54151, 54152, 54153, 267497, 867499). 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.
Sharing Clinical Reports Project (SCRP)	RCV000030973	SCV000053564	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-12-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030973	SCV000144352	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 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
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332086	SCV004040525	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
BRCAlab, Lund University	RCV000030973	SCV004244195	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing