ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4964_4982del (p.Ser1655fs) (rs80359876)

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Total submissions: 20
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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) RCV000031197 SCV000300179 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000123279 SCV000166586 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1655Tyrfs*16) 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 and families affected with breast and ovarian cancer (PMID: 9145677, 26219728, 16847550, 18159056, 26681312). This variant is commonly reported in affected individuals of Calabrian or Sicilian descent (PMID: 11462242, 23199084, 11938448, 17221156). This variant is also known as 5083del19 in the literature. ClinVar contains an entry for this variant (Variation ID: 37616). 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 RCV000130587 SCV000185460 pathogenic Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000159927 SCV000210052 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4964_4982del19 at the cDNA level and p.Ser1655TyrfsX16 (S1655YfsX16) at the protein level. The surrounding sequence is GTGT[del19]ATTT. The deletion causes a frameshift, which changes a Serine to a Tyrosine at codon 1655, and creates a premature stop codon at position 16 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. Also published as BRCA1 5083del19, this variant has been observed in several families with breast and ovarian cancer and has been described as a Calabrian/Southern Italian founder variant (Couch 1997, Ottini 2000, Baudi 2001, Nedelcu 2002, Russo 2007, Janavicius 2010, Finch 2015). We consider BRCA1 c.4964_4982del19 to be pathogenic.
Counsyl RCV000031197 SCV000220918 pathogenic Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159927 SCV000296356 pathogenic not provided 2019-07-25 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031197 SCV000326073 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000466904 SCV000540949 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000123279 SCV000586905 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000123279 SCV000591550 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000123279 SCV000699186 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4964_4982delCTGGCCTGACCCCAGAAGA (p.Ser1655Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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.Ser1796X, c.5417delC, p.Trp1815X, etc.). This variant is absent in 121404 control chromosomes from ExAC. The variant is a recurrent pathogenic variant reported in several HBOC patients/families and in individuals undergoing BRCA1/2 clinical testing. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic.
Mendelics RCV000123279 SCV000839223 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031197 SCV000839896 pathogenic Breast-ovarian cancer, familial 1 2017-05-25 criteria provided, single submitter clinical testing The c.4964_4982del (p.Ser1655Tyrfs*16) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 9145677, 11462242 referred as 5083del19 in some publications]. This variant is considered a founder mutation in Southern Italy [PMID 11462242]. This 19 bp deletion in exon 15 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been detected in the ExAC database . This variant thus classified as pathogenic.
Color RCV000130587 SCV000910928 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000793 SCV001157852 pathogenic not specified 2018-08-31 criteria provided, single submitter clinical testing The BRCA1 c.4964_4982del19; p.Ser1655fs variant (rs80359876), also known as 5083del19, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer (Couch 1997, Finch 2016, Giannini 2006, John 2007), and is considered a founder mutation in Italy (Baudi 2001, Mucaki 2016, Nedelcu 2002, Russo 2007, Russo 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37616), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 19 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional analyses of the variant protein show a truncated protein product and major changes to the transcriptional profile of cells with the variant (Quaresima 2008). Based on available information, the c.4964_4982del19 variant is considered to be pathogenic. References: Baudi F et al. Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer. Hum Mutat. 2001 Aug;18(2):163-4. Couch FJ et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409-15. Finch A et al. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2016 Mar;89(3):304-11. Giannini G et al. Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families. Breast Cancer Res Treat. 2006 Nov;100(1):83-91. John EM et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007 Dec 26;298(24):2869-76. Mucaki EJ et al. A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genomics. 2016 Apr 11;9:19. Nedelcu R et al. BRCA mutations in Italian breast/ovarian cancer families. Eur J Hum Genet. 2002 Feb;10(2):150-2. Russo A et al. BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat. 2007 Nov;105(3):267-76. Russo A et al. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat. 2009 Jan;113(1):67-70. Quaresima B et al. BRCA1 5083del19 mutant allele selectively up-regulates periostin expression in vitro and in vivo. Clin Cancer Res. 2008 Nov 1;14(21):6797-803.
Sharing Clinical Reports Project (SCRP) RCV000031197 SCV000053797 pathogenic Breast-ovarian cancer, familial 1 2013-05-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031197 SCV000145225 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 RCV000123279 SCV000587436 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 RCV000735508 SCV000863646 pathogenic Breast and/or ovarian cancer 2012-11-26 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785419 SCV000923991 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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