Submissions for variant NM_007294.4(BRCA1):c.5252G>C (p.Arg1751Pro)

dbSNP: rs80357442

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567938	SCV000668396	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The p.R1751P variant (also known as c.5252G>C), located in coding exon 18 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5252. The arginine at codon 1751 is replaced by proline, an amino acid with dissimilar properties. In a study using biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with BRCA1 missense variants, this variant was found to have a strong functional effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90). Another 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). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet Med. 2019 01;21:71-80). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378200	SCV001575721	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-17	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 1751 of the BRCA1 protein (p.Arg1751Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (Invitae, external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55482). Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 15172985, 20516115, 30209399, 30765603). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811343	SCV002048248	likely pathogenic	not provided	2024-05-16	criteria provided, single submitter	clinical testing	The BRCA1 c.5252G>C; p.Arg1751Pro variant (rs80357442; ClinVar Variation ID: 55482), to our knowledge, is not reported in the medical literature associated with disease. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. In vitro functional analyses demonstrate defects in transcriptional activity of the BRCA1 protein (Lee 2010). Additionally, a haploid cell survival assay found this variant to be deleterious (Findlay 2018), and a yeast model and fibroblast cell study demonstrated increased cytoplasmic aggregation compared to wildtype (Thouvenot 2016). Computational analyses predict that this variant is deleterious (REVEL: 0.719). Additionally, several computational studies predict this variant to be deleterious (Fernandes 2019, Iversen 2011, Karchin 2007, Mirkovic 2004, Woods 2016). Based on available information, this variant is considered to be likely pathogenic. References: Fernandes VC et al. Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. J Biol Chem. 2019 Apr 12;294(15):5980-5992. PMID: 30765603. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. PMID: 30209399. Iversen ES et al. A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88. PMID: 21447777. Karchin R et al. Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol. 2007 Feb 16;3(2):e26. PMID: 17305420. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. PMID: 20516115. Mirkovic N et al. Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res. 2004 Jun 1;64(11):3790-7. PMID: 15172985. Thouvenot P et al. Yeast cells reveal the misfolding and the cellular mislocalization of the human BRCA1 protein. J Cell Sci. 2016 Dec 1;129(23):4366-4378. PMID: 27802165. Woods NT et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2016;1:16001. PMID: 28781887.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001378200	SCV004227959	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	curation	PS3, PM1, PMS2_sup, PP3. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Findley 2018: LOF, Woods 2016/Fernandes 2019: func. class 5, Lee 2010: strong functional effect, ..., PM1 (medium pathogenic): in BRCT Domain, PM2 (supporting pathogenic): absent from controls, PP3 (supporting pathogenic): PRIOR: 0.66; REVEL: 0.719
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112580	SCV000145413	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2001-10-29	flagged submission	clinical testing
Brotman Baty Institute, University of Washington	RCV000112580	SCV001242474	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro