ClinVar Miner

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

dbSNP: 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 It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 23239986 (2012)). Published functional studies showed that this variant was found to affect the transactivation activity of the protein (PMID: 20516115 (2010), 28781887 (2016)). Additional studies show that this variant causes aberrant splicing resulting in out-of-frame skipping of exon 23 (PMID: 23239986 (2012), 25724305 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic.
Ambry Genetics RCV001024053 SCV001186007 likely pathogenic Hereditary cancer-predisposing syndrome 2022-12-13 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). 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). In addition, this alteration is predicted to be tolerated by in silico analysis. This amino acid position is not well conserved in available vertebrate species. However, RNA experiments demonstrate that this alteration causes out-of-frame skipping of exon 23 (coding exon 21) (Ambry internal data; Wappenschmidt B et al. PLoS ONE. 2012 Dec;7:e50800; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr;150:289-98). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000985440 SCV001247341 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001024053 SCV001352025 likely pathogenic Hereditary cancer-predisposing syndrome 2021-04-19 criteria provided, single submitter clinical testing This missense variant replaces glycine with alanine at codon 1803 of the BRCA1 protein. This variant located in exon 22 at 3 basepairs from the intron 21 splice acceptor site. RNA studies have shown that this variant causes out-of-frame skipping of exon 22 resulting in premature truncation in carrier RNA and corroborated by a minigene splicing assay (PMID: 23239986, 25724305). Functional studies have reported variant impact on transcription activation (PMID: 20516115, 28781887) and no impact in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 23239986; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001326886 SCV001517939 pathogenic Hereditary breast ovarian cancer syndrome 2022-07-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1803 of the BRCA1 protein (p.Gly1803Ala). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 23239986). This variant is also known as 5527G>C. ClinVar contains an entry for this variant (Variation ID: 37668). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 30209399, 30765603). Studies have shown that this missense change results in skipping of exon 22 (also known as exon 23) and introduces a new termination codon (PMID: 23239986, 25724305). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 20104584, 21922593, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031249 SCV000053853 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2012-04-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031249 SCV000145503 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000031249 SCV001243287 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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