ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 28
Download table as spreadsheet
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 2019-12-04 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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000159994 SCV000210185 pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4689C>G at the cDNA level and Tyr1563Ter (Y1563X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also denoted 4808C>G using alternate nomenclature, has been reported in association with familial breast cancer and/or ovarian cancer and is considered pathogenic (Serova 1996, Shih 2002, Turkovic 2010, Schneegans 2012, Wong-Brown 2015).
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048631 SCV000591537 pathogenic Hereditary breast and ovarian cancer syndrome 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 RCV000131835 SCV000683206 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America 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
DNA and Cytogenetics Diagnostics Unit,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 2015-03-09 criteria provided, single submitter clinical testing
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.
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
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 Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.