ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5453A>G (p.Asp1818Gly) (rs80357477)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215390 SCV000274108 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.D1818G variant (also known as c.5453A>G), located in coding exon 21 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5453. The aspartic acid at codon 1818 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in multiple high-risk breast/ovarian cancer families (Rouleau E et al. Cancer Genet Cytogenet. 2010 Oct; 202(2):144-6; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). Further, functional studies using RT-PCR on cDNA have demonstrated complete, allele-specific exon-skipping resulting in a frameshift impacting the second BRCT domain of BRCA1 (Rouleau E et al. Cancer Genet Cytogenet. 2010 Oct; 202(2):144-6; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another functional assay determined the p.D1818G variant to be a loss of function allele (Findlay GM et al. Nature. 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001095362 SCV000324810 likely pathogenic Breast and/or ovarian cancer 2018-03-29 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031253 SCV000326317 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000257937 SCV000699255 pathogenic Hereditary breast and ovarian cancer syndrome 2021-06-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5453A>G (p.Asp1818Gly) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251488 control chromosomes. c.5453A>G has been reported in the literature in multiple families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rouleau_2010, Rebbeck_2018, Parsons_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the predicted amino acid change has limited effects on protein function (e.g. Lee_2010, Fernandes_2019). However, several additional publications report that the variant has an effect on mRNA splicing, resulting in a frameshift and premature stop codon (producing the protein change p.Gly1803GlnfsX11 and resulting in skipping of exon 23), rather than the predicted missense change (e.g. Rouleau_2010, Houdayer_2012, Wai_2020). These findings provide additional evidence for a pathogenic effect. Five ClinVar submitters (evaluation after 2014; including one expert panel) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000215390 SCV000905197 pathogenic Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 1818 of the BRCA1 protein. An RNA study has shown that this variant resulted in the full skipping of exon 22 in carrier RNA, which is predicted to disrupt of the C-terminal portion of the protein including the functionally important second BRCT domain (PMID: 20875879). A functional study has shown that this variant caused loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least four individuals affected with high-risk breast cancer (PMID: 20875879; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000257937 SCV001592632 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1818 of the BRCA1 protein (p.Asp1818Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with unspecified or breast and/or ovarian cancer (PMID: 20875879, 22505045, 29446198). ClinVar contains an entry for this variant (Variation ID: 37672). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 20516115, 30209399). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20875879, 22505045, 30209399). Transcriptional studies using RT-PCR analysis of mRNA isolated from lymphocytes from affected individuals show that this variant results in complete skipping of exon 22 (also known as exon 23 in the literature), and a truncated protein product (p.Gly1803GlnfsX11) (PMID: 20875879, 22505045). This truncation disrupts the C-terminal BRCT domain of the BRCA1 protein, which is important for DNA repair activity (PMID: 14576433, 15133503). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001659906 SCV001878778 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031253 SCV000053857 pathogenic Breast-ovarian cancer, familial 1 2010-12-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031253 SCV000145518 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031253 SCV001243349 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.