Submissions for variant NM_007294.4(BRCA1):c.1838G>A (p.Arg613Lys)

gnomAD frequency: 0.00001  dbSNP: rs786203937

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167455	SCV000218311	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	clinical testing	The p.R613K variant (also known as c.1838G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1838. The arginine at codon 613 is replaced by lysine, an amino acid with highly similar properties. This variant has been detected in multiple unrelated patients with breast and/or ovarian cancer (Mannan AU et al. J Hum Genet, 2016 Jun;61:515-22; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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.
Invitae	RCV000473402	SCV000549408	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 613 of the BRCA1 protein (p.Arg613Lys). 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: 187705). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26911350, 29470806). This variant is present in population databases (rs786203937, gnomAD 0.006%).
Color Diagnostics, LLC DBA Color Health	RCV000167455	SCV000909362	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283892	SCV001469376	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251084 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in at least one individual/family with breast and/or ovarian cancer (PMIDs: 26911350 (2016) and 29470806 (2018)). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167455	SCV003849706	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).