ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4243del (p.Glu1415fs) (rs80357981)

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Total submissions: 12
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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) RCV000031159 SCV000300095 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000217565 SCV000274996 pathogenic Hereditary cancer-predisposing syndrome 2017-05-09 criteria provided, single submitter clinical testing 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 RCV000031159 SCV000325906 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482127 SCV000566521 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.4243delG at the cDNA level and p.Glu1415LysfsX4 (E1415KfsX4) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 c.4362delG. The normal sequence, with the base that is deleted in brackets, is ACTA[delG]AAGC. The deletion causes a frameshift, which changes a Glutamic Acid to a Lysine at codon 1415, and creates a premature stop codon at position 4 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.4243delG has been observed in at least four breast and/or ovarian cancer families and in an individual with endometrial cancer (Konecny 2011, Smith 2011, Lu 2015). In an HDR activity assay, BRCA1 c.4243delG demonstrated significantly reduced HDR activity relative to wild type (Lu 2015). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000496518 SCV000591499 pathogenic Hereditary breast and ovarian cancer syndrome 2014-12-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000482127 SCV000883469 pathogenic not provided 2017-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482127 SCV000888913 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing
Color RCV000217565 SCV001345619 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496518 SCV001362810 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4243delG (p.Glu1415LysfsX4) 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. The variant allele was found at a frequency of 4e-06 in 251428 control chromosomes (gnomAD). c.4243delG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Smith_2011, Konecny_2011, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of HDR activity (Lu_2015). Six ClinVar submissions including an expert panel, ENIGMA, (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031159 SCV000053759 pathogenic Breast-ovarian cancer, familial 1 2012-06-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031159 SCV000145038 pathogenic Breast-ovarian cancer, familial 1 2003-07-22 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496518 SCV000587384 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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