ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs80357981
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Total submissions: 15
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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, susceptibility to, 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 2021-08-19 criteria provided, single submitter clinical testing The c.4243delG pathogenic mutation, located in coding exon 11 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4243, causing a translational frameshift with a predicted alternate stop codon (p.E1415Kfs*4). This pathogenic mutation has been reported in several unrelated breast and/or ovarian cancer families (Smith LD et al. Breast Cancer Res. 2011 Jan 31;13(1):R14; Konecny M et al. Breast Cancer Res Treat. 2011 Feb;126(1):119-30; Machackova E et al. Klin Onkol. 2019;32:51-71). Of note, this alteration is also designated as 4362delG 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031159 SCV000325906 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482127 SCV000566521 pathogenic not provided 2022-11-23 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: significant reduction in HDR activity compared to wild-type (Lu C et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4362del; This variant is associated with the following publications: (PMID: 29625052, 21203900, 21281505, 26689913, 24312913, 16267036, 28452373, 29452958, 30720243, 29922827)
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 Diagnostics, LLC DBA Color Health RCV000217565 SCV001345619 pathogenic Hereditary cancer-predisposing syndrome 2023-08-17 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 12 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 at least one individual affected with breast cancer (PMID: 21281505) and in several suspected hereditary breast and ovarian cancer families (PMID: 21203900, 29446198, 31409081). This variant has been identified in 1/251428 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496518 SCV001362810 pathogenic Hereditary breast 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.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000482127 SCV001449883 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
Invitae RCV000496518 SCV001579487 pathogenic Hereditary breast ovarian cancer syndrome 2023-08-28 criteria provided, single submitter clinical testing This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 21203900, 21281505). This variant is present in population databases (rs80357981, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu1415Lysfs*4) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is also known as c.4362delG. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37578).
Sharing Clinical Reports Project (SCRP) RCV000031159 SCV000053759 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-06-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031159 SCV000145038 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354027 SCV000591499 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu1415LysfsX4 variant was identified in 4 of 2104 proband chromosomes (frequency: 0.002) from individuals or families with Hereditary Breast and ovarian Cancer (Konecny 2011, Smith 2011). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 67690 chromosomes (frequency: 1.48e-05) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The variant was also identified in dbSNP (ID: rs80357981) “With Pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, as pathogenic by BIC ), GeneInsight VariantWire(1X, classified as pathogenic by a clinical laboratory), the BIC database (2X with clinical importance). The p.Glu1415LysfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1415 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer 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.
CZECANCA consortium RCV001271022 SCV001451836 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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