ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1603G>A (p.Gly535Arg)

dbSNP: rs1555591488
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478072 SCV000600258 uncertain significance not provided 2023-07-21 criteria provided, single submitter clinical testing In the published literature, this variant has been described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in individuals with BRCA1-related disorders. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae RCV000559550 SCV000635804 uncertain significance Hereditary breast ovarian cancer syndrome 2017-08-27 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 535 of the BRCA1 protein (p.Gly535Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has not been reported in the literature in individuals with BRCA1-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
University of Washington Department of Laboratory Medicine, University of Washington RCV003157611 SCV003851181 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).
Ambry Genetics RCV003157611 SCV004004369 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-04 criteria provided, single submitter clinical testing The p.G535R variant (also known as c.1603G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1603. The glycine at codon 535 is replaced by arginine, 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.

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