ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5030_5034CTAAT[1] (p.Leu1679fs) (rs80357623)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575406 SCV000660952 pathogenic Hereditary cancer-predisposing syndrome 2017-07-19 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) RCV000031205 SCV000145268 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Color RCV000575406 SCV000905028 pathogenic Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031205 SCV000326113 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000483893 SCV000702500 pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031205 SCV000282336 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 RCV000483893 SCV000568056 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA1 is denoted c.5035_5039delCTAAT at the cDNA level and p.Leu1679TyrfsX2 (L1679YfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAT[delCTAAT]TACT. The deletion causes a frameshift, which changes a Leucine to a Tyrosine at codon 1679, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.5035_5039delCTAAT, also published as BRCA1 5154del5 using alternate nomenclature, has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Musolino 2005, John 2007, Veschi 2007, Azzollini 2016, Pellegrino 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000048742 SCV000918793 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5035_5039delCTAAT (p.Leu1679TyrfsX2) 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 (e.g. p.Glu1694X and p.Tyr1703X). The variant was absent in 246172 control chromosomes (gnomAD). c.5035_5039delCTAAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000048742 SCV000076755 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1679Tyrfs*2) 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 with a personal and/or family history of breast and ovarian cancer (PMID: 16457150, 17591842). This variant is also known as 5154del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37624). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048742 SCV000967736 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-19 criteria provided, single submitter clinical testing The p.Leu1679TyrfsX2 variant in BRCA1 has been reported in more than 10 individu als with hereditary breast and/or ovarian cancer (HBOC), as well as one young re portedly unaffected individual (<35 years old) with a family history of HBOC (Mu solino 2005, John 2007, Veschi 2007, Azzollini 2016, Breast Information Core (BI C): https://research.nhgri.nih.gov/bic/). This variant was absent from large pop ulation studies. The p.Leu1679TyrfsX2 variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 1679 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (SCV000282336.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal d ominant manner based upon presence in multiple affected individuals, absence fro m the general population, and the predicted impact on the protein. ACMG/AMP Crit eria applied: PVS1, PM2, PS4_Moderate.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031205 SCV000296371 pathogenic Breast-ovarian cancer, familial 1 2015-08-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483893 SCV000887708 pathogenic not provided 2015-08-03 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048742 SCV000587445 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031205 SCV000053805 pathogenic Breast-ovarian cancer, familial 1 2011-06-17 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.