ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1196A>G (p.His399Arg)

dbSNP: rs587780794
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000123266 SCV000166573 uncertain significance Hereditary breast ovarian cancer syndrome 2023-05-21 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 399 of the BRCA1 protein (p.His399Arg). This variant is present in population databases (rs587780794, gnomAD 0.0009%). 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: 136078). 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. 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 RCV000563126 SCV000664803 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-21 criteria provided, single submitter clinical testing The p.H399R variant (also known as c.1196A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1196. The histidine at codon 399 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 RCV000563126 SCV003846112 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).

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