Submissions for variant NM_007294.4(BRCA1):c.1510C>T (p.Arg504Cys)

gnomAD frequency: 0.00001  dbSNP: rs80357445

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047505	SCV000075518	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 504 of the BRCA1 protein (p.Arg504Cys). This variant is present in population databases (rs80357445, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26219265, 28525389). ClinVar contains an entry for this variant (Variation ID: 54277). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 36833189). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000129280	SCV000184040	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.R504C variant (also known as c.1510C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1510. The arginine at codon 504 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in a Greek woman with a personal history of breast cancer (Apessos A et al. Cancer Genet 2018 Jan;220:1-12). Additionally, several papers have predicted that this alteration will affect protein function based primarily on sequence conservation through evolution (Burk-Herrick A et al. Mamm Genome. 2006 Mar; 17(3):257-70; Ramirez CJ et al. Oncogene. 2004 Mar; 23(9):1780-8; Fleming MA et al. Proc Natl Acad Sci U S A. 2003 Feb; 100(3):1151-6). However, one functional study reported that this alteration had no significant deviations in protein expression, proteasomal degradation, stability, or subcellular localization (Hovland HN et al. Genes (Basel). 2023 Jan;14(2)). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588157	SCV000293215	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Ronowicz et al., 2015; Dougherty et al., 2017); Published functional studies do not demonstrate a damaging effect (Hovland et al., 2023); Also known as 1629C>T; This variant is associated with the following publications: (PMID: 15385441, 16518693, 12531920, 16267036, 15001988, 29310832, 32377563, 29884841, 15343273, 20104584, 28525389, 26219265, 31911673, 31853058, 36833189)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588157	SCV000600254	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	The BRCA1 c.1510C>T (p.Arg504Cys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 26219265 (2015), 28525389 (2017), 29310832 (2018)). In one individual with breast cancer, this variant was reported to co-occur with a pathogenic variant in the BRCA2 gene, which suggests this variant is not the primary cause of disease (PMID: 26219265 (2015)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID: 36833189 (2023)). The frequency of this variant in the general population, 0.000059 (3/50674 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000237007	SCV000698870	uncertain significance	not specified	2019-08-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1510C>T (p.Arg504Cys) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510C>T has been reported in the literature in individuals affected with or being tested for Hereditary Breast and Ovarian Cancer (Judkins_2005, Ronowicz_2015, Apessos_2018, Dougherty_2017). Co-occurrence with other pathogenic variant has been reported (BRCA2, p.Asn3124Ile), providing supporting evidence for a benign role (Ronowicz_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129280	SCV000912050	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 504 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28525389, 29310832), and this variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000154). This variant has been identified in 4/282442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588157	SCV002009467	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129280	SCV003851248	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV004803957	SCV004818315	uncertain significance	BRCA1-related cancer predisposition	2024-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 504 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 28525389, 29310832), and this variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000154). This variant has been identified in 4/282442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111635	SCV000144117	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2001-10-29	no assertion criteria provided	clinical testing
Faculty of Pharmacy, Medical University of Gdansk	RCV000207331	SCV000262647	uncertain significance	Familial cancer of breast	2014-02-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354022	SCV000591340	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg504Cys variant was not identified in affected individuals in the literature, but was identified in dbSNP (ID# rs80357445) “with untested allele”, in the Exome Variant Server ESP Project with a frequency of 0.0002 in African American alleles, in BIC 1x as a variant of unknown clinical importance, and in the LOVD database. The p.Arg504 residue is not conserved in mammals and lower organisms, and the variant amino acid (Cys) is present in cow, increasing the likelihood this is a benign variant. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Two in silico evolutionary conservation studies suggest that the variant affects protein function (Fleming 2003, Ramirez 2004), while another similar study yielded inconclusive results (Burk-Herrick 2006). Additionally, the authors of these three studies note that the variant may confer oncogenic risk as it occurs within one of the BRCA1 nuclear localization sites. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS).
BRCAlab, Lund University	RCV000111635	SCV004244126	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing