Submissions for variant NM_007294.4(BRCA1):c.2266A>G (p.Arg756Gly)

dbSNP: rs1064795091

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479150	SCV000570556	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2266A>G at the cDNA level, p.Arg756Gly (R756G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). Using alternate nomenclature, this variant would be defined as BRCA1 2385A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg756Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg756Gly occurs at a position that is not conserved and is located within the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Arg756Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775002	SCV000909098	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV001045834	SCV001209708	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-17	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 421371). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 756 of the BRCA1 protein (p.Arg756Gly).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000775002	SCV003847802	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).