ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4603G>T (p.Glu1535Ter) (rs80357366)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162879 SCV000213366 pathogenic Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Baylor Genetics RCV000048603 SCV000540929 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077578 SCV000145126 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077578 SCV000326006 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077578 SCV000300141 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000235132 SCV000210179 pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4603G>T at the cDNA level and p.Glu1535Ter (E1535X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 c.4722G>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 individuals with breast, ovarian, and uterine cancer (Schorge 2001, Pennington 2013, Dodova 2015, Rummel 2017). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000496846 SCV000699159 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: The variant in interest, c.4603G>T, is a nonsense mutation that leads to a premature termination at codon 1535. This variant has been reported in the literature and reputable databases at least 15 times and was not identified in large and broad ExAC control cohort. This variant is located in a close proximity to other known pathogenic variants, such as c.4609C>T (p.Gln1537X), c.4612C>T (p.Gln1538X), c.4618G>T (p.Glu1540X) and c.4621G>T (p.Glu1541X). These variants have been reported in UMD, BIC and HGMD at least 7 times with biological significance "5 - Causal", indicating that the variant in interest is located in a mutational hot spot. The variant in interest shows very strong evidence for pathogenicity: it is a truncating variant, located in a mutational hot spot and is absent from controls (ESP and 1000G). Taken together, this variant has been classified as a Pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496846 SCV000587411 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077578 SCV000109381 pathogenic Breast-ovarian cancer, familial 1 2012-09-25 no assertion criteria provided clinical testing

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