ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2999del (p.Glu1000fs) (rs80357991)

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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) RCV000083193 SCV000282297 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048036 SCV000076049 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1000Glyfs*24) 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 observed in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 14732925, 21324516). This variant is also known as 3118delA in the literature. ClinVar contains an entry for this variant (Variation ID: 54744). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083193 SCV000325519 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000479376 SCV000568135 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.2999delA at the cDNA level and p.Glu1000GlyfsX24(E1000GfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTAG[delA]GGAA. The deletion causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 1000, and creates a premature stop codon at position 24 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2999delA, also published as 3118delA using alternate nomenclature, has been in association with breast and ovarian cancer (Risch 2006, John 2007, Spearman 2008). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479376 SCV000600310 pathogenic not provided 2017-03-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017870 SCV001179032 pathogenic Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000048036 SCV001362811 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2999delA (p.Glu1000GlyfsX24) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.3026C>A, p.Ser1009X; c.3181delA, p.Ile1061fsX1; c.4222C>T, p.Gln1408X). The variant was absent in 245960 control chromosomes (gnomAD). The variant, c.2999delA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000083193 SCV000115267 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083193 SCV000144604 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 RCV000048036 SCV000587269 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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