ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3661G>T (p.Glu1221Ter) (rs80357310)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162864 SCV000213351 pathogenic Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA1) RCV000112149 SCV000144828 pathogenic Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148388 SCV000190086 pathogenic Neoplasm of the breast 2014-06-01 no assertion criteria provided research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112149 SCV000325716 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048276 SCV000591461 pathogenic Hereditary breast and ovarian cancer syndrome 2012-12-13 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112149 SCV000299989 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
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
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.
Integrated Genetics/Laboratory Corporation of America RCV000048276 SCV000699055 pathogenic Hereditary breast and 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.
Invitae RCV000048276 SCV000076289 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs80357310, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9150151, 21553119, 25452441, 26541979). This variant is also known as 3780G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54957). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048276 SCV000587329 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000112149 SCV000297602 pathogenic Breast-ovarian cancer, familial 1 2013-01-17 no assertion criteria provided clinical testing

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