ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1658A>G (p.His553Arg)

gnomAD frequency: 0.00001  dbSNP: rs748431827
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001213831 SCV001385481 uncertain significance Hereditary breast ovarian cancer syndrome 2024-04-05 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 553 of the BRCA1 protein (p.His553Arg). This variant is present in population databases (rs748431827, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 943608). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001732072 SCV001983626 uncertain significance not specified 2021-09-19 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV003158496 SCV003851141 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 RCV003158496 SCV005100935 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-14 criteria provided, single submitter clinical testing The p.H553R variant (also known as c.1658A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1658. The histidine at codon 553 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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