ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1961dup (p.Tyr655fs) (rs80357522)

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Total submissions: 16
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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) RCV000031018 SCV000282270 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 RCV000203641 SCV000075674 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr655Valfs*18) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357853, ExAC 0.01%). This variant has been observed in individuals with breast, ovarian, and prostate cancer (PMID: 7837387, 21324516, 22516946, 22970155, 21559243). This variant is also known as 2080insA in the literature. ClinVar contains an entry for this variant (Variation ID: 54417). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130225 SCV000185065 pathogenic Hereditary cancer-predisposing syndrome 2018-01-04 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)
GeneDx RCV000047661 SCV000210018 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.1961dupA at the cDNA level and p.Tyr655ValfsX18 (Y655VfsX18) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]GTAC. The duplication causes a frameshift, which changes a Tyrosine to a Valine at codon 655, and creates a premature stop codon at position 18 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.1961dupA, also reported as 1954dupA or 2080insA using alternate nomenclature, has been reported in association with breast and ovarian cancer (Shattuck-Eidens 1995, Liede 2002, Alansari 2009, Zhang 2011, Couch 2015) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047661 SCV000296401 pathogenic not provided 2015-10-23 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031018 SCV000325203 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031018 SCV000564296 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000203641 SCV000591358 pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-23 criteria provided, single submitter clinical testing
Color RCV000130225 SCV000683004 pathogenic Hereditary cancer-predisposing syndrome 2016-08-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000203641 SCV000698902 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-26 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1961dupA (p.Tyr655Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate EIN3 and BCRT domains. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2001dupA, p.Ser713X, c.2515C, etc.). This variant was found in 2/121294 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant is a pathogenic variant reported in several HBOC patients/families in literature and clinical databases. Several clinical diagnostic laboratories/reputable databases have also classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
3DMed Clinical Laboratory Inc RCV000677810 SCV000803969 pathogenic Ovarian cancer 2018-04-08 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000130225 SCV000992226 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Sharing Clinical Reports Project (SCRP) RCV000031018 SCV000053611 pathogenic Breast-ovarian cancer, familial 1 2010-07-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031018 SCV000144261 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000203641 SCV000587175 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735521 SCV000863659 pathogenic Breast and/or ovarian cancer 2014-01-13 no assertion criteria provided clinical testing

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