ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1486C>A (p.Arg496Ser)

dbSNP: rs28897676
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001364594 SCV001560750 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-29 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 496 of the BRCA1 protein (p.Arg496Ser). This variant is present in population databases (rs28897676, gnomAD 0.01%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 19029836). ClinVar contains an entry for this variant (Variation ID: 54267). 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 with a negative predictive value of 95%. 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.
Ambry Genetics RCV002390197 SCV002701626 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-26 criteria provided, single submitter clinical testing The p.R496S variant (also known as c.1486C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 1486. The arginine at codon 496 is replaced by serine, an amino acid with dissimilar properties. This alteration has been identified in 1/66 pancreatic cancer patients who also had family history of at least two additional relatives with pancreatic cancer (Axilbund JE et al. Cancer Biol Ther, 2009 Jan;8:131-5). This amino acid position is poorly 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002390197 SCV003851263 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).
Breast Cancer Information Core (BIC) (BRCA1) RCV000111628 SCV000144108 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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