ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5503C>T (p.Arg1835Ter) (rs41293465)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 33
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) RCV000077627 SCV000282345 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 RCV000203652 SCV000077033 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the BRCA1 mRNA at codon 1835 (p.Arg1835*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 28 amino acids of the BRCA1 protein, including a portion of the C-terminal BRCT-C functional domain (PMID: 22843421, 11157798). This variant is not present in population databases (rs41293465, ExAC no frequency). This variant has been observed in many individuals and families affected with breast, ovarian, and bladder cancer (PMID: 27553291, 8554067, 10486320, 11802209, 16683254, 19949876, 23704984). This variant is also known as 5622C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55601). Experimental studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it disrupts chromatin structure by increasing chromatin unfolding, a marker of impaired BRCA1 function (PMID: 11739404). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131862 SCV000186917 pathogenic Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing The p.R1835* pathogenic mutation (also known as c.5503C>T), located in coding exon 22 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5503. This changes the amino acid from an arginine to a stop codon within coding exon 22. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Rashid MU et al. BMC Cancer. 2016 08;16:673; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48:58-63; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Apessos A et al. Cancer Genet. 2018 01;220:1-12). Of note, this alteration is also designated as 5622C>T 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. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000049020 SCV000210227 pathogenic not provided 2021-05-24 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 12360400, 24504028, 16998791, 8554067, 25682074, 26541979, 25085752, 26898890, 26848529, 21559243, 17591843, 11260866, 9796975, 27767231, 25066507, 16683254, 27553291, 20727672, 26404129, 10505028, 18465347, 10486320, 26028024, 25722380, 27157322, 12601471, 12960223, 18375895, 11920621, 16782705, 12393792, 24578176, 9760198, 20104584, 24728189, 27194814, 23569316, 16644204, 11739404, 11802209, 9667259, 10699917, 16528604, 26976419, 24249303, 19949876, 23704984, 28324225, 29339979, 29752822, 29470806, 28724667, 28993434, 30209399, 29310832, 30702160, 29446198, 31090900, 31528241, 30855176, 30291343, 29176636)
Counsyl RCV000077627 SCV000220880 likely pathogenic Breast-ovarian cancer, familial 1 2014-11-14 criteria provided, single submitter literature only
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240766 SCV000265868 pathogenic Breast neoplasm 2015-11-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000049020 SCV000296284 pathogenic not provided 2020-02-20 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.
GeneKor MSA RCV000238956 SCV000296784 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Arginine to a termination codon at amino acid residue 1835 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735447 SCV000324836 pathogenic Breast and/or ovarian cancer 2015-09-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077627 SCV000326344 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131862 SCV000537638 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000077627 SCV000564353 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000203652 SCV000699267 pathogenic Hereditary breast and ovarian cancer syndrome 2020-12-28 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5503C>T (p.Arg1835X) 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. The variant allele was found at a frequency of 1.2e-05 in 251278 control chromosomes. c.5503C>T has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, 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. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077627 SCV000743370 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077627 SCV000744581 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000049020 SCV000806977 pathogenic not provided 2017-11-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000049020 SCV001247339 pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000049020 SCV001446590 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000049020 SCV001449724 pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001664134 SCV001877310 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
Sharing Clinical Reports Project (SCRP) RCV000077627 SCV000109430 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077627 SCV000145551 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000077627 SCV000238467 pathogenic Breast-ovarian cancer, familial 1 2015-03-20 no assertion criteria provided research The heterozygous variant in the BRCA1 gene (c.5503C>T; p.Arg1835*)is considered pathogenic. This change results in a premature stop codon interrupting an important functional domain BRCT2 (PMID: 11739404) and premature truncation results in impaired function. This variant has been previously published in 2 individuals of Punjabi ethnicity and part of a cohort of unrelated Pakistani individuals with breast and ovarian cancer (PMID: 16998791), though the paper has no additional information on the phenotype of the affected individuals. This variant has also been seen in multiple affected individuals by other clinical labs (SCV000109430, SCV000145551, SCV000186917, SCV000210227, SCV000077033).
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000203652 SCV000587514 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353835 SCV000591636 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg1835X variant is reported in the literature in 12/7062 proband chromosomes of individuals with breast and ovarian cancer (Bellacosa 2010, Borg 2010, Dizin 2006, Evans 2003, Ferla 2007, Frank 1998, Magnard 2002, Ramus 2007, Rashid 2006, Spurdle 2008); it was not found in any of the 484 control chromosomes. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs#:41293465) but no frequency information was provided, and is therefore, not very informative for assessing the population frequency. The alteration leads to a premature stop codon at position 1835 which is predicted to lead to a truncated or absent protein and loss of function, which is an established disease mechanism for the BRCA1 gene in hereditary breast and ovarian cancer. The variant is reported in the BIC database (x66) and UMD database (x20) as a variant of clinical significance. In addition, two functional studies using the yeast two-hybrid screen and glutathione-S-transferase (GST) pull-down assay, determined that the variant abolished interaction of BRCA1 with two proteins: Acetyl Coenzyme A (CoA) Carboxylase and PABP (Dizin 2006, Magnard 2002). In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077627 SCV000733584 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735447 SCV000863583 pathogenic Breast and/or ovarian cancer 2012-07-14 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785213 SCV000923781 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000077627 SCV001237592 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
University Health Network,Princess Margaret Cancer Centre RCV001527479 SCV001738497 pathogenic Familial cancer of breast; Neoplasm of ovary; Lung cancer 2021-03-19 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554249 SCV001774816 pathogenic Breast carcinoma 2021-08-08 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000049020 SCV001905715 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000049020 SCV001955746 pathogenic not provided no assertion criteria provided clinical testing

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.