ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4183C>T (p.Gln1395Ter) (rs80357260)

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Total submissions: 23
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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) RCV000077564 SCV000282324 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000212181 SCV000210169 pathogenic not provided 2020-11-10 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; 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 4302C>T; This variant is associated with the following publications: (PMID: 31528241, 31090900, 30322717, 29161300, 29446198, 29907814, 30720243, 29470806, 28135048, 26911350, 26681312, 27553291, 27425403, 26986251, 16287141, 25722380, 20104584, 16683254, 24728189, 19941162, 21559243, 25452441, 17949280, 14672397, 27225819, 24504028, 23772696, 16998791, 16847550, 26014432, 8531967, 22006311)
Ambry Genetics RCV000162874 SCV000213361 pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing The p.Q1395* pathogenic mutation (also known as c.4183C>T), located in coding exon 10 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4183. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been extensively reported in the literature in individuals with a personal and/or family history of breast and/or ovarian and/or peritoneal cancer and/or colon cancer and associated with somatic loss of heterozygosity (Langston AA et al. N Engl J Med. 1996 Jan 18;334(3):137-42; Walsh T et al. Proc Natl Acad Sci. U S A. 2011 Nov 1;108(44):18032-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Rashid MU et al. BMC Cancer. 2016 08;16:673; Alemar B et al. Cancer Genet. 2016 09;209(9):417-422; Alemar B et al. PLoS ONE. 2017 Nov;12(11):e0187630; Palermo E et al. Sci Rep. 2018 Jun;8(1):9188; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196; Soyano AE et al. Clin Colorectal Cancer. 2018 12;17(4):e647-e650), as well as in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR Hum. Mutat. 2018 05;39(5):593-620). This alteration has also been shown to be highly prevalent in the Tyrolean population of Austria (Pölsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). 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.
Counsyl RCV000077564 SCV000220260 likely pathogenic Breast-ovarian cancer, familial 1 2014-04-21 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212181 SCV000296397 pathogenic not provided 2020-07-22 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077564 SCV000325875 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162874 SCV000683156 pathogenic Hereditary cancer-predisposing syndrome 2021-02-02 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 11 of the BRCA1 gene, creating a premature translation stop signal in the BRCA1 protein. 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 observed in individuals affected with breast and ovarian cancer (PMID: 8531967, 16760289, 16847550, 22711857, 24728189, 26014432, 26681312, 27553291, 29470806, 30322717, 31090900) and is reported to be a founder mutation in the Tyrolean population in Austria (PMID: 26014432). This variant has been identified in 1/242836 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 RCV000496276 SCV000699114 pathogenic Hereditary breast and ovarian cancer syndrome 2021-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4183C>T (p.Gln1395X) 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 4.1e-06 in 245892 control chromosomes. c.4183C>T has been 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. Multiple clinical diagnostic laboratories, one expert panel (ENIGMA) and a consortium (CIMBA) 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.
Mendelics RCV000496276 SCV000839239 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000778172 SCV000914330 pathogenic Familial cancer of breast 2019-01-30 criteria provided, single submitter research
Mendelics RCV000077564 SCV001140532 pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212181 SCV001247350 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212181 SCV001447558 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Invitae RCV000496276 SCV001581780 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1395*) 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 variant has been reported in individuals and families affected with breast cancer, ovarian cancer and peritoneal carcinoma (PMID: 8531967, 24504028, 27553291, 26681312, 22006311). This variant is also known as 4302C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55125). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001662250 SCV001877210 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) RCV000077564 SCV000109366 pathogenic Breast-ovarian cancer, familial 1 2012-09-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077564 SCV000145005 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000077564 SCV000212002 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496276 SCV000587380 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353792 SCV000591497 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Gln1395X variant has been previously reported in the literature in 2 of 512 proband chromosomes from individuals with hereditary breast and ovarian cancer and absent from 100 control chromosomes (Langston 1996, Rashid 2006). In addition, this variant is reported in the BIC database 28x as clinically important and the UMD database 35x as causal. This variant leads to a premature stop codon at position 1395, which is predicted to lead to a truncated or absent protein product and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077564 SCV000733613 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735467 SCV000863604 pathogenic Breast and/or ovarian cancer 2013-08-09 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000212181 SCV001906261 pathogenic not provided no assertion criteria provided clinical testing

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