Submissions for variant NM_007294.4(BRCA1):c.1837A>G (p.Arg613Gly)

dbSNP: rs863224753

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001087756	SCV000254958	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220811	SCV000275529	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The p.R613G variant (also known as c.1837A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1837. The arginine at codon 613 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000484390	SCV000571683	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1837A>G at the cDNA level, p.Arg613Gly (R613G) 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 1956A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg613Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg613Gly occurs at a position that is not conserved and is located in the NLS2 motif and a region of interaction with multiple proteins (Borg 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg613Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000220811	SCV000909363	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 613 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484390	SCV001133501	uncertain significance	not provided	2018-11-28	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466464	SCV002761580	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-12-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220811	SCV003849708	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).
PreventionGenetics, part of Exact Sciences	RCV003417722	SCV004114336	uncertain significance	BRCA1-related condition	2023-06-14	criteria provided, single submitter	clinical testing	The BRCA1 c.1837A>G variant is predicted to result in the amino acid substitution p.Arg613Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is classified as likely benign and uncertain clinical significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/216655/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.