ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3228_3229del (p.Gly1077fs)

dbSNP: rs80357635
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Total submissions: 21
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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) RCV000031097 SCV000282299 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000225762 SCV000076120 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly1077Alafs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357635, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11720839, 14522380, 15477862, 16030099, 17574839, 17591843, 18819001, 18821011, 19837273, 19941167, 20104584, 22798144, 24549055, 26350514). It is commonly reported in individuals of Norwegian ancestry (PMID: 11720839, 14522380, 15477862, 16030099, 17574839, 17591843, 18819001, 18821011, 19837273, 19941167, 20104584, 22798144, 24549055, 26350514). This variant is also known as 3347delAG and c.3228delAG. ClinVar contains an entry for this variant (Variation ID: 37516). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000048107 SCV000210036 pathogenic not provided 2023-06-22 criteria provided, single submitter clinical testing Founder pathogenic variant in the Norwegian population (Ferla 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3347_3348del, 3345delAG, and 3347delAG; This variant is associated with the following publications: (PMID: 10359546, 24549055, 20104584, 26350514, 27356891, 27425403, 27836010, 29061375, 29339979, 29907814, 34413315, 32438681, 31336956, 29922827, 28888541, 19656164, 17591843, 10660329, 18821011, 14522380, 17574839, 15477862, 18819001, 22798144, 17063270, 10595257, 24312913, 15735322, 26852130, 23776375, 24131976, 19383375, 9544766, 12543786, 15519522, 18158280, 16764716, 28161869, 28637432, 28127413, 28664506, 29470806, 28724667, 29161300, 30702160, 28111427, 30720243, 32854451, 31825140, 33646313, 32719484, 11720839, 35710434, 35864222, 34981296)
Ambry Genetics RCV000162862 SCV000213349 pathogenic Hereditary cancer-predisposing syndrome 2021-10-10 criteria provided, single submitter clinical testing The c.3228_3229delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3228 to 3229, causing a translational frameshift with a predicted alternate stop codon (p.G1077Afs*8). This mutation has been reported in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Aretini P et al. Breast Cancer Res Treat, 2003 Sep;81:71-9; Bjørge T et al. Br. J. Cancer, 2004 Nov;91:1829-34; Ottini L et al. Breast Cancer Res Treat, 2009 Aug;116:577-86; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13; Lin PH et al. Oncotarget, 2016 Feb;7:8310-20; Alemar B et al. Cancer Genet, 2016 09;209:417-422; Høberg-Vetti H et al. Eur J Hum Genet, 2016 06;24:881-8; Grindedal EM et al. BMC Cancer, 2017 Jun;17:438; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Fanale D et al. Cancers (Basel), 2020 Aug;12; Santonocito C et al. Cancers (Basel), 2020 May;12; Incorvaia L et al. Ther Adv Med Oncol, 2020 Dec;12). Due to its prevalence in Norway and Tuscany, this alteration has also been recognized as a founder mutation in these two populations (Møller P et al. Eur. J. Cancer. 2001 Dec;37:2428-34; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504). Of note, this alteration is also designated as c.3226_3227delAG, 3347delAG and 3345delAG in the 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.
Counsyl RCV000031097 SCV000220429 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-06-18 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048107 SCV000296418 pathogenic not provided 2021-08-26 criteria provided, single submitter clinical testing This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 34072659 (2021), 32854451 (2020), 18821011 (2009), and 11720839 (2001)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031097 SCV000325582 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000473763 SCV000540936 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031097 SCV000564392 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-11-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162862 SCV000683092 pathogenic Hereditary cancer-predisposing syndrome 2023-07-06 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 30 individuals and families affected with breast and/or ovarian cancer (PMID: 11720839, 14522380, 14531499, 15477862, 17574839, 18819001, 18821011, 19837273, 20104584, 22798144, 24549055, 26350514, 27425403, 28637432, 28724667, 29371908, 33471991; Leiden Open Variation Database DB-ID BRCA1_000674), and it is considered a founder or recurrent mutation in the Norwegian and Italian populations (PMID: 17591843, 18821011). This variant has been identified in 61 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/250376 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 RCV000225762 SCV000699008 pathogenic Hereditary breast ovarian cancer syndrome 2023-11-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3228_3229delAG (p.Gly1077AlafsX8) 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. The variant allele was found at a frequency of 4e-06 in 250376 control chromosomes. c.3228_3229delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Papi_2009, Moller_2007). 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. The following publications have been ascertained in the context of this evaluation (PMID: 18821011, 17574839). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000048107 SCV001450357 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000048107 SCV001905568 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000225762 SCV002025962 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798030 SCV002043438 pathogenic Breast and/or ovarian cancer 2020-06-17 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000048107 SCV003818071 pathogenic not provided 2022-09-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000031097 SCV004216856 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-12-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031097 SCV000053693 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-11-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031097 SCV000144682 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000225762 SCV000587285 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
BRCAlab, Lund University RCV000031097 SCV004244061 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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