ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.66dupA (p.Glu23Argfs) (rs80357783)

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Total submissions: 22
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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) RCV000031272 SCV000282347 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 RCV000049087 SCV000077100 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu23Argfs*18) 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 and families with breast and/or ovarian cancer (PMID: 8595420, 12181777, 16998791, 20189727, 24916970). This variant is also known as 185insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37691). 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 RCV000163427 SCV000213973 pathogenic Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing The c.66dupA pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of one nucleotide at position 66, causing a translational frameshift with a predicted alternate stop codon (p.E23Rfs*18). This mutation has been described in numerous breast and ovarian cancer patients and families (Couch FJ and Weber BL. Hum. Mutat. 1996;8:8-18; Rashid MU et al. Int. J. Cancer. 2006 Dec;119:2832–39; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bujassoum SM et al. J. Cancer Sci. Ther. 2017;9(2):358-64). Of note, this alteration is also designated as 185insA 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000478017 SCV000227401 pathogenic not provided 2014-09-05 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240681 SCV000265852 pathogenic Breast neoplasm 2015-11-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478017 SCV000296291 pathogenic not provided 2019-03-15 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031272 SCV000326376 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031272 SCV000488962 pathogenic Breast-ovarian cancer, familial 1 2016-07-26 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031272 SCV000564309 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000478017 SCV000564708 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA1 is denoted c.66dupA at the cDNA level and p.Glu23ArgfsX18 (E23RfsX18) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTT[dupA]GAGT. The duplication causes a frameshift, which changes a Glutamic Acid to an Arginine at codon 23, and creates a premature stop codon at position 18 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.66dupA, also known as BRCA1 185dupA or 185insA using alternate nomenclature, has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer (Kroiss 2005, Rashid 2006, Thirthagiri 2008, Noel 2010, Ginsburg 2011, Peixoto 2014, Heramb 2018). We consider this variant to be pathogenic.
GeneKor MSA RCV000478017 SCV000693501 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change inserts one nucleotide in exon 2 of BRCA1 mRNA (c.66dupA), causing a frameshift at codon 23 and the creation of a premature translation stop signal 18 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant is also known as 185insA in the literature and it has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 8595420, 20189727, 24916970, 16998791). The mutation database ClinVar contains entries for this variant (Variation ID: 37691).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049087 SCV000699283 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.66dupA (p.Glu23Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. p.Gln60X, p.Tyr101X, p.Glu143X, etc.). This variant is absent in 120930 control chromosomes from ExAC. The variant is a recurrent pathogenic variant found in several HBOC patients/families and in individuals undergoing BRCA1/2 testing. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Mendelics RCV000049087 SCV000839318 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163427 SCV000911363 pathogenic Hereditary cancer-predisposing syndrome 2020-08-17 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 2 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 25863477, 26187060, 27257965, 29470806, 29907814). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000778174 SCV000914333 pathogenic Familial cancer of breast 2019-01-30 criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000031272 SCV001499756 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031272 SCV000053877 pathogenic Breast-ovarian cancer, familial 1 2013-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031272 SCV000144170 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 RCV000049087 SCV000587005 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785198 SCV000923766 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000778174 SCV000925806 pathogenic Familial cancer of breast 2018-11-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000478017 SCV001552235 uncertain significance not provided no assertion criteria provided clinical testing

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