Submissions for variant NM_007294.4(BRCA1):c.115T>C (p.Cys39Arg)

dbSNP: rs80357164

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077483	SCV000244296	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077483	SCV000324971	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077483	SCV000488027	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-28	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000077483	SCV000577916	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570028	SCV000665362	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-11	criteria provided, single submitter	clinical testing	The p.C39R pathogenic mutation (also known as c.115T>C), located in coding exon 2 of the BRCA1 gene, results from a T to C substitution at nucleotide position 115. The cysteine at codon 39 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple hereditary breast and/or ovarian cancer families (Rostagno P et al. J. Hum. Genet., 2003 Jul;48:362-6; Machackova E et al. BMC Cancer, 2008 May;8:140; Konecny M et al. Breast Cancer Res. Treat., 2011 Feb;126:119-30). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). One other functional study has demonstrated that p.C39R causes abolishment and decreased activity of ubiquitin protein ligase function in the BRCA1 RING finger in vitro (Morris JR et al. Hum. Mol. Genet., 2006 Feb;15:599-606). Additional functional studies using yeast assays have shown that this mutation results in deficient protein compared to wild-type BRCA1 (Thouvenot P et al. PLoS Genet., 2016 06;12:e1006096). The p.C39R alteration is located in a critical region of the BRCA1 protein RING domain, and, along with other alterations at this codon including p.C39Y and p.C39S, has been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this alteration has also been designated as 234T>C in published literature. Based on the supporting evidence to date, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985365	SCV001133477	pathogenic	not provided	2018-12-05	criteria provided, single submitter	clinical testing	Statistically enriched in patients compared to ethnically matched controls. Not found in the total gnomAD dataset, and the data is high quality (0/282180 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077483	SCV001435001	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-02-01	criteria provided, single submitter	clinical testing	The c.115T>C (p.Cys39Arg) variant in the BRCA1 gene has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 12827452, 18489799, 28993434). This variant is absent from large databases of genetic variation in the general population. Functional classification using saturation genome editing showed that this variant to be loss-of-function (PMID 30209399). Multiple lines of prediction algorithms support the deleterious effect of the variant. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, c.115T>C (p.Cys39Arg) variant in the BRCA1 gene is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496824	SCV001586683	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-10	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 22843421, 24489791, 25823446). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 39 of the BRCA1 protein (p.Cys39Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12827452, 15024741, 18489799, 21203900, 26822949). ClinVar contains an entry for this variant (Variation ID: 54152). 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. 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: 9808526, 11320250, 17262179, 18500671, 19504351, 23683081, 25823446). 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.
GeneDx	RCV000985365	SCV001804196	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impairs E2 and BARD1 binding and reduces E3 ubiquitin ligase activity (Morris et al., 2006; Starita et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with Hereditary Breast and Ovarian Cancer syndrome (Rostagno et al., 2003; Machackova et al., 2008; Sweet et al., 2010; Konecny et al., 2011; Lhota et al., 2016; Ng et al., 2016; Wen et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 234T>C; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 15235020, 22753008, 26822949, 26757417, 18493658, 30040829, 29884136, 21990134, 15024741, 18489799, 24489791, 21203900, 12827452, 27272900, 16403807, 25823446, 19543972, 30209399, 29446198, 28993434, 33087888, 24389207, 20104584, 8944023)
Sema4, Sema4	RCV000570028	SCV002538000	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000077483	SCV002761700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-01-02	criteria provided, single submitter	clinical testing	The BRCA1 c.115T>C variant is classified as Pathogenic (PS1, PS3, PM2, PP5) The BRCA1 c.115T>C variant is a single nucleotide change in the BRCA1 gene, which is predicted to change the amino acid cysteine at position 39 in the protein to arginine. This variant is absent from population databases (PM2). Well-established functional studies show a deleterious effect of this variant (PS3). Assay of Cys39 to Tyr and Arg indicate affect on double strand break repair and centrosome duplication. This variant results in the same amino acid change as a previously established variant (PS1). All changes from cysteine regarded as pathogenic - cysteine involved in disulphide bridge The variant has been reported in dbSNP (rs80357164) and in the HGMD database: CM040687. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 54152).
All of Us Research Program, National Institutes of Health	RCV000077483	SCV004839116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved cysteine with arginine at codon 39 in the RING domain 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 ubiquitin ligase, homology-directed repair, haploid cell proliferation assays and binding assays to known protein-protein interacting partners (PMID: 16403807, 25823446, 30209399, 30219179, 37168384). This variant has been reported in over 10 individuals and families affected with breast and/or ovarian cancer (PMID: 12827452, 15024741, 17319787, 18489799, 19543972, 26757417, 30287823). Several different missense substitutions at p.Cys39 has been reported as disease-causing in ClinVar (variation ID: 37392, 37393, 54151, 54153, 267497). This variant has not been identified 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)	RCV000077483	SCV000109281	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-07-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077483	SCV000144349	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	RCV000496824	SCV000587013	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077483	SCV001241900	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
CZECANCA consortium	RCV001270963	SCV001451767	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000077483	SCV005061295	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control