ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3661G>T (p.Glu1221Ter)

dbSNP: rs80357310
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Total submissions: 19
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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) RCV000112149 SCV000299989 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000048276 SCV000076289 pathogenic Hereditary breast ovarian cancer syndrome 2023-09-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54957). This variant is also known as 3780G>T. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 21553119, 25452441, 26541979). This variant is present in population databases (rs80357310, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Glu1221*) 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).
GeneDx RCV000258961 SCV000210152 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.3661G>T at the cDNA level and p.Glu1221Ter (E1221X) at the protein level. The substitution creates a nonsense variant, changing a Glutamic Acid to a premature stop codon (GAA>TAA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as 3780G>T using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Peelen 1997, Dong 1998, Claes 2004, De Leeneer 2012, Hasmad 2015) and is considered pathogenic.
Ambry Genetics RCV000162864 SCV000213351 pathogenic Hereditary cancer-predisposing syndrome 2024-01-10 criteria provided, single submitter clinical testing The p.E1221* pathogenic mutation (also known as c.3661G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3661. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been identified in multiple cohorts of individuals diagnosed with breast, ovarian and pancreatic cancer and has been recognized as a founder mutation in the Belgian population (Peelen T et al. Am. J. Hum. Genet. 1997 May;60:1041-9; Claes K et al. Br. J. Cancer. 2004 Mar;90:1244-51; Janaviius R. EPMA J. 2010 Sep;1:397-412; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Hasmad HN et al. Gynecol. Oncol., 2016 05;141:318-322; Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390; Blair AB et al. J. Am. Coll. Surg., 2018 04;226:630-637.e1; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Li A et al. Gynecol. Oncol., 2018 10;151:145-152). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15) and was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this mutation is also designated as 3780G>T in the 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 RCV000112149 SCV000325716 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048276 SCV000699055 pathogenic Hereditary breast ovarian cancer syndrome 2016-03-28 criteria provided, single submitter clinical testing Variant summary: This c.3661G>T variant results in a premature termination codon in exon 10, predicted to cause a truncated or absent BRCA1 protein. Heterozygous loss-of-function due to mutations in this gene is an established disease mechanism in HBOC or HBOC-related cancers. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Glu1373X, p.Gln1395X, p.Tyr1853X, etc.). This variant was found in 1/121338 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0010005) in this gene. This variant has been reported in several patients with HBOC in literature and clinical databases. Multiple clinical labs as well as reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant or Pathogenic.
Revvity Omics, Revvity RCV000258961 SCV002020156 pathogenic not provided 2019-03-05 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000258961 SCV002585645 pathogenic not provided 2022-08-01 criteria provided, single submitter clinical testing BRCA1: PVS1, PM2
Baylor Genetics RCV000112149 SCV004216985 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-03-24 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162864 SCV004360220 pathogenic Hereditary cancer-predisposing syndrome 2021-11-16 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a 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 10 individuals affected with breast, ovarian or pancreatic cancer (PMID: 11733976, 11802209, 15026808, 25452441, 26541979, 30078507, 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA1_001444) and in two dozen families suspected to be affected with hereditary breast and ovarian cancer (PMID: 9150151, 9760198, 29446198). This variant also has been described as a recurrent mutation in individuals affected with breast and ovarian cancer from Belgium (PMID: 15026808). This variant has been identified in 1/251298 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112149 SCV000144828 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1999-12-30 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148388 SCV000190086 pathogenic Breast neoplasm 2014-06-01 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000112149 SCV000297602 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2013-01-17 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000048276 SCV000587329 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353431 SCV000591461 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Glu1221X variant has been previously reported in the literature in at least 8 of 4008 chromosomes from individuals with hereditary breast and ovarian cancer (Baeyens 2004, Claes 2004, Judkins 2005, Meindl 2002 , Peelen 1997). It has also been observed in public databases including BIC (9x as clinically important) and in the UMD (1x). The variant was also reported in dbSNP and in the exome variant server 1 in 8599 eurapean alleles and may be a low frequency pathogenic variant (rs80357310). The p.Glu1221X variant leads to a premature stop codon at position 1221, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are a known mechanism of mutation in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735476 SCV000863613 pathogenic Breast and/or ovarian cancer 2013-08-26 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000258961 SCV001744841 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000258961 SCV001958336 pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004758627 SCV005343368 pathogenic BRCA1-related disorder 2024-03-18 no assertion criteria provided clinical testing The BRCA1 c.3661G>T variant is predicted to result in premature protein termination (p.Glu1221*). This variant has been reported in individuals with breast cancer and ovarian cancer or pancreatic cancer (examples, Table 1. Claes et al 2004. PubMed ID: 15026808; Supplementary Table 2. Couch et al 2014. PubMed ID: 25452441; eTable 1. Blair et al 2018. PubMed ID: 29309945). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic in ClinVar including expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/54957/). In summary, this variant is interpreted as pathogenic.

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