ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1961dup (p.Tyr655fs) (rs80357522)

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Total submissions: 17
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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 2019-10-31 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 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 2020-01-15 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001357 SCV001158555 pathogenic not specified 2019-06-20 criteria provided, single submitter clinical testing The BRCA1 c.1961dupA; p.Tyr655fs variant (rs80357522), also reported as 2080insA, has been described in multiple individuals and families affected with hereditary breast and ovarian cancer (HBOC), including prostate cancer (Heramb 2018, Leongamornlert 2012, Shattuck-Eidens 1995, Singh 2018, Sun 2017, Zhang 2011). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 54417) and is observed on only three alleles in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Leongamornlert D et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012 May 8;106(10):1697-701. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995 Feb 15;273(7):535-41. Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
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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