ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2019del (p.Glu673fs) (rs80357626)

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Total submissions: 13
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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) RCV000077504 SCV000282271 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 RCV000047685 SCV000075698 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu673Aspfs*28) 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: 12112655, 14871810, 16683254, 23635950) and is a common cause of the disease in the Dutch population (PMID: 24307375, 16683254). This variant is also known as 2137delA and 2138delA in the literature. ClinVar contains an entry for this variant (Variation ID: 54438). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000167502 SCV000218360 pathogenic Hereditary cancer-predisposing syndrome 2016-08-24 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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077504 SCV000325214 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077504 SCV000564341 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000479187 SCV000568424 pathogenic not provided 2017-09-05 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.2019delA at the cDNA level and p.Glu673AspfsX28 (E673DfsX28) at the protein level. Using alternate nomenclature, this variant has previously been published as BRCA1 2138delA and 2137delA. The normal sequence, with the base that is deleted in braces, is AAGA[A]CCTG. The deletion causes a frameshift which changes a Glutamic Acid to an Aspartic Acid at codon 673, and creates a premature stop codon at position 28 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.2019delA has been reported in multiple individuals with personal and/or family histories of breast and ovarian cancer and is a common pathogenic variant in the Dutch population (Yazici 2002, Szabo 2004, Hermsen 2006, Jacobi 2007, Dobricic 2013, Brohet 2014). We consider this variant to be pathogenic.
Color RCV000167502 SCV000688362 pathogenic Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047685 SCV000698907 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-13 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2019delA (p.Glu673Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If the variant escapes NMD, it is predicted to truncate BCRT domain (InterPro, UniProt). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1135X, p.Gln1200X, p.Glu1250X, etc.). This variant is absent from 121362 control chromosomes from ExAC. This variant has been reported in multiple affected HBOC patients/families in literature and clinical databases. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077504 SCV000744667 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077504 SCV000109304 pathogenic Breast-ovarian cancer, familial 1 2008-03-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077504 SCV000144278 pathogenic Breast-ovarian cancer, familial 1 2011-03-02 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047685 SCV000587179 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077504 SCV000733650 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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