ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5213G>A (p.Gly1738Glu)

dbSNP: rs80357450
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048864 SCV000076877 pathogenic Hereditary breast ovarian cancer syndrome 2022-12-31 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1738 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 10811118, 11157798, 20516115). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55462). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 18465347, 21918854, 23113073). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1738 of the BRCA1 protein (p.Gly1738Glu).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077609 SCV000326221 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000077609 SCV000564324 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-07-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001190130 SCV001357548 pathogenic Hereditary cancer-predisposing syndrome 2021-07-21 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 1738 of the BRCA1 protein. Computational and in silico lines of evidence consistently support a deleterious effect on the function of the gene or gene product (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant protein is defective in assays for protease sensitivity, peptide binding, phospho-peptide specificity, transcriptional activation, and a haploid cell proliferation (PMID: 10811118, 11157798, 20516115, 30209399). This variant has been reported in individuals and families affected breast cancer and ovarian cancer (PMID: 11157798, 18465347, 21918854, 23113073, 30678073, 23113073). It has been shown that this variant segregates with breast cancer in two families, including one family with five breast cancer affected members across three generations (PMID: 23113073). Variant results in a different missense amino acid change in same location as a previously established pathogenic variant (p.Gly1738Arg). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048864 SCV001363823 pathogenic Hereditary breast ovarian cancer syndrome 2019-08-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5213G>A (p.Gly1738Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.5213G>A has been reported in the literature in several individuals and families affected with Hereditary Breast and Ovarian Cancer (Keshavarzi_2012, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated protein folding defect, compromised phosphopeptide binding, and decreased transcriptional activity in yeast and human cells (Hayes_2000, Lee_2010). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and they classified the variant as pathogenic (2x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000077609 SCV001745220 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-07-04 criteria provided, single submitter clinical testing A 46-year-old female whit metastatic unilateral breast cancer (IDC). she has history of breast cancer in her second degree relatives (her paternal aunts).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003321494 SCV004026750 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000077609 SCV004216999 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-02-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077609 SCV000109412 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-08-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077609 SCV000145397 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000077609 SCV001237929 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
BRCAlab, Lund University RCV000077609 SCV002588828 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-26 no assertion criteria provided clinical testing

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