ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4689C>G (p.Tyr1563Ter) (rs80357433)

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Total submissions: 34
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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) RCV000031188 SCV000282332 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 RCV000048631 SCV000076644 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1563*) 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 particular variant has been reported in the literature in individuals affected with hereditary breast and ovarian cancer (PMID: 8554067, 23110154, 25066507, 20727672, 27167707). This variant is also known as 4808C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37607). 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 RCV000131835 SCV000186890 pathogenic Hereditary cancer-predisposing syndrome 2018-11-13 criteria provided, single submitter clinical testing The p.Y1563* pathogenic mutation (also known as c.4689C>G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4689. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Iyevleva AG et al. Cancer Lett. 2010 Dec;298:258-63; Schneegans S et al. Fam. Cancer. 2012 Jun;11:181-8​; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Pern F et al. PLoS One. 2012;7:e47993; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620), and a history weighing algorithm classified it as pathogenic (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). One study demonstrated that this mutation triggers nonsense mediated decay (NMD) and results in less than half the amount of BRCA1 mRNA compared to wild-type (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14). Of note, this alteration is also designated as 4808C>G 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 RCV000159994 SCV000210185 pathogenic not provided 2021-05-17 criteria provided, single submitter clinical testing Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Serova 1996, Shih 2002, Turkovic 2010, Schneegans 2012, Wong-Brown 2015, Nguyen-Dumont 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4808C>G; This variant is associated with the following publications: (PMID: 27167707, 30128899, 29422015, 30551077, 11844822, 8554067, 22160602, 23110154, 25556971, 24830819, 25682074, 26843898, 25948282, 25085752, 29339979, 28324225, 29907814, 29446198, 30487145, 30216591, 30322717, 20807450, 30612635, 32072338, 29625052, 31447099)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000159994 SCV000226313 pathogenic not provided 2015-05-14 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031188 SCV000267714 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031188 SCV000296307 pathogenic Breast-ovarian cancer, familial 1 2015-03-09 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031188 SCV000326033 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031188 SCV000488572 pathogenic Breast-ovarian cancer, familial 1 2016-04-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000464295 SCV000540932 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031188 SCV000564327 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000031188 SCV000593676 pathogenic Breast-ovarian cancer, familial 1 2016-05-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131835 SCV000683206 pathogenic Hereditary cancer-predisposing syndrome 2020-09-14 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 15 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: BIC database, 20807450, 22160602, 23110154, 25066507, 25452441, 27167707, 29446198). This variant has been identified in 1/250704 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.
GeneKor MSA RCV000159994 SCV000693540 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1563 (p.Tyr1563*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with hereditary breast and ovarian cancer (PMID: 8554067, 23110154, 25066507, 20727672, 27167707). This sequence change is also known as 4808C>G in the literature. This particular variant has been described in the mutation database ClinVar (Variation ID: 37607) as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048631 SCV000699164 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4689C>G (p.Tyr1563X) 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 250704 control chromosomes (gnomAD). c.4689C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Alsop_2012, Bergman_2005, Couch_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 21 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031188 SCV000743389 pathogenic Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031188 SCV000744610 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000159994 SCV000806958 pathogenic not provided 2016-03-03 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031188 SCV000839898 pathogenic Breast-ovarian cancer, familial 1 2017-06-06 criteria provided, single submitter clinical testing The c.4689C>G (p.Tyr1563*) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 8554067, 23110154]. This variant creates a premature stop codon at amino acid position 1563 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant is thus classified as pathogenic.
Snyder Lab, Genetics Department,Stanford University RCV000031188 SCV000853089 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159994 SCV000888922 pathogenic not provided 2019-08-28 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000353 SCV001157089 pathogenic not specified 2019-05-13 criteria provided, single submitter clinical testing The BRCA1 c.4689C>G; p.Tyr1563Ter variant (rs80357433), also known as 4808C>G, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer (Pern 2012, Rebbeck 2018, Schneegans 2012, Serova 1996). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Pern F et al. Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One. 2012;7(10):e47993. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Schneegans SM Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 Jun;11(2):181-8. Serova O et al. A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am J Hum Genet. 1996 Jan;58(1):42-51.
Institute of Human Genetics, University of Leipzig Medical Center RCV000031188 SCV001440857 pathogenic Breast-ovarian cancer, familial 1 2021-08-26 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000159994 SCV001450206 pathogenic not provided 2017-02-22 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000159994 SCV001715198 pathogenic not provided 2020-07-24 criteria provided, single submitter clinical testing PVS1, PM2, PP5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000159994 SCV001747802 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659861 SCV001877260 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000159994 SCV001905671 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031188 SCV000053788 pathogenic Breast-ovarian cancer, familial 1 2013-03-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031188 SCV000145160 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 RCV000048631 SCV000587421 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159994 SCV000591537 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031188 SCV000733607 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785416 SCV000923988 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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