ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs) (rs80359454)

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Total submissions: 16
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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) 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.
Invitae RCV000195401 SCV000072434 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-26 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.
Ambry Genetics RCV000131081 SCV000186011 pathogenic Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing The c.4478_4481delAAAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4478 to 4481, causing a translational frameshift with a predicted alternate stop codon (p.E1493Vfs*10). This pathogenic mutation has been reported in multiple families affected with breast, ovarian, and/or prostate cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer 2011 Oct;105:1230-4; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26). Of note, this alteration is also designated as 4706del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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.
Counsyl RCV000077327 SCV000220668 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-04 criteria provided, single submitter literature only
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
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044421 SCV000600589 pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508471 SCV000602836 pathogenic not specified 2016-11-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131081 SCV000683623 pathogenic Hereditary cancer-predisposing syndrome 2020-08-24 criteria provided, single submitter clinical testing This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Thi variant has been reported in individuals affected with ovarian cancer (PMID: 11972384, 20406929, 21324516, 22711857, 23165508, 23791828, 24728189) and breast cancer (PMID: 20950396, 22798144). This variant has been identified in 4/250362 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
St. Jude 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.
Sharing Clinical Reports Project (SCRP) RCV000077327 SCV000109124 pathogenic Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077327 SCV000146433 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354234 SCV001548796 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Glu1493Valfs*10 variant was identified in 12 of 17460 proband chromosomes (frequency: 0.0007) from individuals or families with prostate, breast or ovarian cancer (Beetstra 2006, Ding 2011, Fong 2010, Kim 2012, Kote-Jarai 2011, Lubinski 2004, Peto 1999, Risch 2001, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359454) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and twelve other submitters), LOVD 3.0 (19x as pathogenic ), and UMD-LSDB (1x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant was shown to have a partial response to platinum-based therapy according to the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup Response criteria (Fong 2010). The c.4478_4481del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1493 and leads to a premature stop codon at position 1502. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer (HBOC) and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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