Submissions for variant NM_007294.4(BRCA1):c.2268G>T (p.Arg756Ser)

dbSNP: rs80356884

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240783	SCV000265874	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000777927	SCV000913981	likely benign	Hereditary cancer-predisposing syndrome	2016-11-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777927	SCV001175768	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-25	criteria provided, single submitter	clinical testing	The p.R756S variant (also known as c.2268G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2268. The arginine at codon 756 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Peixoto A et al. Fam Cancer, 2006 Jul;5:379-87; Zhong X et al. PLoS One, 2016 Jun;11:e0156789; Zhang Y et al. BMC Cancer, 2022 Aug;22:842). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043803	SCV001207568	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 756 of the BRCA1 protein (p.Arg756Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary breast, ovarian, and/or prostate cancer (PMID: 27257965, 30702160, 34326862, 35918668). ClinVar contains an entry for this variant (Variation ID: 224428). 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: 35196514). 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.
GeneDx	RCV001753632	SCV001994911	uncertain significance	not provided	2020-02-10	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history including breast cancer (Peixoto 2006, Zhong 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.2387G>T; This variant is associated with the following publications: (PMID: 16826315, 30702160, 27257965, 24916970, 31825140)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000777927	SCV003847797	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	RCV003997694	SCV004818207	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753632	SCV005626034	uncertain significance	not provided	2024-10-24	criteria provided, single submitter	clinical testing	The BRCA1 c.2268G>T (p.Arg756Ser) variant has been reported in the published literature in several individuals affected with breast and/or ovarian cancer (PMIDs: 27257965 (2016), 32566972 (2020), 32803532 (2020), 35918668 (2022)). It has also been reported in affected individuals, but not in reportedly healthy individuals, in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). This variant was found with the BRCA2 c.1294del deleterious variant in an individual affected with breast cancer (PMID: 35864222 (2022)), suggesting that the BRCA1 c.2268G>T variant may not be the cause of disease. One functional study reported that this variant is functional in homology-directed DNA repair (PMID: 35196514 (2022)), however further research is necessary. The frequency of this variant in the general population, 0.000004 (1/251210 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250597	SCV002520887	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only