ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 19
Download table as spreadsheet
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 2020-08-26 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 The c.1961dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.Y655Vfs*18). This mutation has been reported in numerous breast, ovarian, or prostate cancer patients (Shattuck-Eidens D et al. JAMA 1995 Feb;273:535-41; Couch FJ et al. Hum. Mutat. 1996;8:8-18; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Leongamornlert D et al. Br. J. Cancer 2012 May;106:1697-701; Couch FJ et al. J Clin Oncol. 2015 Feb 1;33(4):304-11). This mutation was also detected in a 45 year old male Pakistani patient with clear cell renal cell carcinoma and an extensive family history of early onset breast, uterine, prostate, ureter, colon, lung, bladder, liver, brain, oral, bone, and kidney cancers (Rashid MU et al. Fam. Cancer, 2011 Dec;10:709-12). Of note, this alteration is also designated as 2080insA and c.1945dupA in 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.
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 Health, Inc RCV000130225 SCV000683004 pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2080insA and c.1961insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 7837387, 12181777, 17688236, 18340530, 21324516, 22970155, 24728189, 31161121). This variant also has been reported in individuals affected with prostate and renal cell carcinoma (PMID: 21751003, 22516946). This variant has been identified in 3/250730 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000047661 SCV001450388 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001660192 SCV001877528 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
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

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.