ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4474_4477AAAG[1] (p.Glu1493fs) (rs80359454)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508471 SCV000602836 pathogenic not specified 2016-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131081 SCV000186011 pathogenic Hereditary cancer-predisposing syndrome 2017-05-19 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077327 SCV000146433 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722037 SCV000853214 pathogenic Diffuse intrinsic pontine glioma 2017-06-09 criteria provided, single submitter clinical testing This is a frameshift alteration in which four nucleotides are deleted (coding nucleotides 4478 through 4481) and is predicted to change a Glutamic Acid to a Valine at amino acid codon 1493, shift the reading frame and result in a premature stop codon 10 amino acids downstream. Classification criteria: PVS1, PM2, PP1.
Color RCV000131081 SCV000683623 pathogenic Hereditary cancer-predisposing syndrome 2016-12-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077327 SCV000327042 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077327 SCV000220668 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-04 criteria provided, single submitter literature only
Department of Pathology and Molecular Medicine,Queen's University RCV000195401 SCV000588092 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077327 SCV000282393 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000044421 SCV000210810 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.4478_4481delAAAG at the cDNA level and p.Glu1493ValfsX10 (E1493VfsX10) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAG[delAAAG]TGTC. The deletion causes a frameshift, which changes a Glutamic Acid to a Valine at codon 1493, and creates a premature stop codon at position 10 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. BRCA2 c.4478_4481delAAAG, previously reported as 4706_4709delAAAG, 4706del4, or 4705del4 using alternate nomenclature, has been observed in association with hereditary breast and ovarian cancer (Tavtigian 1996, Meindl 2002, Ginsburg 2011, Zhang 2011, Kim 2012, Dudley 2018) as well as early-onset prostate cancer (Kote-Jarai 2011). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000195401 SCV000694775 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 variant, c.4478_4481delAAAG (p.Glu1493Valfs), causes a frameshift resulting in a premature stop codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable clinical laboratories/databases cite the variant with a classification of "pathogenic." Therefore, the variant of interest is classified as Pathogenic.
Invitae RCV000195401 SCV000072434 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1493Valfs*10) in the BRCA2 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 and families affected with female breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 8589730, 21324516, 22798144, 21952622, 15131399, 11179017, 20927582). This variant is also known as 4706del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 51653). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044421 SCV000600589 pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195401 SCV000587714 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077327 SCV000109124 pathogenic Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing

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