ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5080G>T (p.Glu1694Ter) (rs80356896)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077593 SCV000300196 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048780 SCV000076793 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1694*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in patients affected with breast and/or ovarian cancer (PMID: 9333265, 9497265). In the literature, this variant is also known as 5199G>T. ClinVar contains an entry for this variant (Variation ID: 55387). In addition, experimental studies have demonstrated that this nonsense variant leads to the skipping of exon 17 (also called exon 18 in the literature) during mRNA splicing and results in the in-frame deletion of 26 amino acids (p.Asp1692_Phe1717del) from the BRCA1 protein. The deletion of these amino acids disrupts the conserved BRCT protein domain and is expected to be deleterious (PMID: 9497265). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255531 SCV000321439 pathogenic not provided 2015-03-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5080G>T at the cDNA level and p.Glu1694Ter (E1694X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG). BRCA1 c.5080G>T is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. However in vivo and in vitro assays have shown that this mutation results in complete skipping of exon 17, previously described as exon 18 using alternate exon numbering, which is due to the disruption of a splicing enhancer. The complete skipping of this exon results in an in-frame deletion of 26 amino acids; however, the skipping of exon 17 results in disruption of the first BRCT domain making it unlikely that the BRCA1 protein can remain functional (Perrin-Vidoz 2002, Liu 2001, Mazoyer 1998). Additionally, BRCA1 c.5080G>T, also published as 5199G>T using alternate nomenclature, has been reported in several individuals with Hereditary Breast and Ovarian Cancer syndrome (Shattuck-Eidens 1997, Liu 2001, Schoumacher 2001, Meindl 2002, Kim 2012). Based on current information, we consider this BRCA1 c.5080G>T to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077593 SCV000326151 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000580802 SCV000683251 pathogenic Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077593 SCV000744601 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077593 SCV000109396 pathogenic Breast-ovarian cancer, familial 1 2006-11-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077593 SCV000145303 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048780 SCV000587458 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077593 SCV000733600 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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