ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5408G>C (p.Gly1803Ala) (rs80357149)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985440 SCV001133630 likely pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/277218 chr). Found in at least one symptomatic patient. Predicted to have a tolerated effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Ambry Genetics RCV001024053 SCV001186007 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing The p.G1803A variant (also known as c.5408G>C), located in coding exon 21 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5408. The glycine at codon 1803 is replaced by alanine, an amino acid with similar properties. This alteration was reported in several German families with a clinical history suggestive of hereditary breast and ovarian cancer (Wappenschmidt B et al. PLoS ONE. 2012 Dec;7:e50800; personal communication). Functional assays with the protein harboring the missense change demonstrated that this alteration has no effect on protein folding, binding activity or binding specificity, but may have compromised transactivation activity (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Woods NT et al. Genomic Medicine. 2016: 1:16001). 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. However, RT-PCR with patient leukocytes and minigene analyses both demonstrate that this alteration causes out-of-frame skipping of exon 23 (coding exon 21) (Wappenschmidt B et al. PLoS ONE. 2012 Dec;7:e50800; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr;150:289-98). A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J. Biol. Chem.. 2019 04;294:5980-5992). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000985440 SCV001247341 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001024053 SCV001352025 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing
Invitae RCV001326886 SCV001517939 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1803 of the BRCA1 protein (p.Gly1803Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 23239986). This variant is also known as 5527G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37668). This variant has been reported not to substantially affect BRCA1 protein function (PMID: 30209399). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23239986, 25724305). 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.
Sharing Clinical Reports Project (SCRP) RCV000031249 SCV000053853 uncertain significance Breast-ovarian cancer, familial 1 2012-04-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031249 SCV000145503 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031249 SCV001243287 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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