ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1384G>A (p.Gly462Arg) (rs80357221)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047451 SCV000075464 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 462 of the BRCA1 protein (p.Gly462Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs80357221, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 54230). An experimental study has shown that this missense change results in only a modest reduction of the homology-directed repair (HDR) activity of the BRCA1 protein in vitro (PMID: 26689913). 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 RCV000129965 SCV000184789 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000289723 SCV000329121 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1384G>A at the cDNA level, p.Gly462Arg (G462R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). Using alternate nomenclature, this variant would be defined as BRCA1 1503G>A. BRCA1 Gly462Arg was observed to result in reduced homology-directed repair activity, compared to wild type (Lu 2015). Consistent with splicing predictions, this variant was not found to alter splicing in a mini-gene assay (Anczukow 2008). BRCA1 Gly462Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly462Arg occurs at a position that is conserved across species and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether BRCA1 Gly462Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000077488 SCV000784902 uncertain significance Breast-ovarian cancer, familial 1 2017-02-14 criteria provided, single submitter clinical testing
Color RCV000129965 SCV000903582 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077488 SCV000109286 uncertain significance Breast-ovarian cancer, familial 1 2009-04-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077488 SCV000144074 uncertain significance Breast-ovarian cancer, familial 1 1997-09-15 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148410 SCV000190109 uncertain significance Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research

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