ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4117G>T (p.Glu1373Ter) (rs80357259)

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Total submissions: 14
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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) RCV000031150 SCV000300075 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 RCV000048449 SCV000076462 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1373*) 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 individuals affected with breast and ovarian cancer (PMID: 17591842, 11179017, 26219728). This variant is also known as 4236G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37569). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074589 SCV000108674 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4117G>T at the cDNA level and p.Glu1373Ter (E1373X) at the protein level. Using alternate nomenclature this variant would be defined as BRCA1 4236G>T. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple families with clinical histories consistent with hereditary breast and ovarian cancer syndrome (Nedelcu 2002, Kadouri 2007, Veschi 2007, Grant 2015, Lolas Hamameh 2017). We consider this variant to be pathogenic.
Ambry Genetics RCV000162872 SCV000213359 pathogenic Hereditary cancer-predisposing syndrome 2019-02-27 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031150 SCV000325854 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000162872 SCV000537657 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048449 SCV000591492 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-05 criteria provided, single submitter clinical testing
Counsyl RCV000031150 SCV000677652 pathogenic Breast-ovarian cancer, familial 1 2015-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074589 SCV001133576 pathogenic not provided 2018-11-23 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV000048449 SCV001363929 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-28 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.4117G>T (p.Glu1373X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 243608 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer , Hereditary Breast and Ovarian Cancer and high grade serous ovarian cancer (Nedelcu_2002, Kadouri_2007, Capalbo_2006, Marchetti_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031150 SCV000053750 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031150 SCV000144987 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 RCV000048449 SCV000587375 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735478 SCV000863615 pathogenic Breast and/or ovarian cancer 2002-03-21 no assertion criteria provided clinical testing

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