ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2679_2682del (p.Lys893fs) (rs80357596)

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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) RCV000031062 SCV000282286 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 RCV000047925 SCV000075938 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys893Asnfs*106) 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 observed in patients with breast and ovarian cancer (PMID: 9145677, 22006311). It is also known as c.2798delGAAA in the literature. ClinVar contains an entry for this variant (Variation ID: 37481). 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 RCV000131877 SCV000186932 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing The c.2679_2682delGAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2679 to 2682, causing a translational frameshift with a predicted alternate stop codon (p.K893Nfs*106). This mutation has been detected in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Rummel S et al. Breast Cancer Res. Treat. 2013 Jan;137:119-25; Singer CF et al. Clin. Genet. 2014 Jan;85:72-5). Of note, this alteration is also designated as 2798del4 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.
Counsyl RCV000031062 SCV000220601 likely pathogenic Breast-ovarian cancer, familial 1 2014-08-19 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255129 SCV000296315 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000255129 SCV000321421 pathogenic not provided 2020-08-12 criteria provided, single submitter clinical testing 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; Identified in individuals with personal and family histories of breast and/or ovarian cancer (Couch 1997, Borg 2010, Walsh 2011, Alsop 2012, Deng 2019, Ashour 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 2798del4 or 2795del4; This variant is associated with the following publications: (PMID: 22006311, 9145677, 8622478, 26187060, 22711857, 20104584, 28497333, 30972954, 31372034, 27062684, 32341426, 31825140, 31090900)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031062 SCV000325426 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000047925 SCV000605741 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-28 criteria provided, single submitter clinical testing The p.Lys893fs variant in BRCA1 has been reported in >50 individuals with BRCA1- associated cancers (Couch 1997, Wagner 1998, Borg 2012, Walsh 2011, Lecarpentier 2012, Breast Cancer Information Core (BIC) database) and was absent from large population studies, though the ability of these studies to accurately detect ind els may be limited. This variant is predicted to cause a frameshift, which alter s the protein?s amino acid sequence beginning at position 893 and leads to a pre mature termination codon 106 amino acids downstream. Heterozygous loss of functi on of the BRCA1 gene is an established disease mechanism in individuals with her editary breast and ovarian cancer (HBOC). In summary, this variant meets our cri teria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Color Health, Inc RCV000131877 SCV000683052 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031062 SCV000803347 pathogenic Breast-ovarian cancer, familial 1 2018-05-22 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047925 SCV000918689 pathogenic Hereditary breast and ovarian cancer syndrome 2021-05-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2679_2682delGAAA (p.Lys893AsnfsX106) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250972 control chromosomes. c.2679_2682delGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (ie. Alsop_2012, Couch_1997, Rummel_2013, Roberston_2012, Wagner_1996, etc). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001190 SCV001158346 pathogenic not specified 2019-04-03 criteria provided, single submitter clinical testing The BRCA1 c.2679_2682delGAAA; p.Lys893fs variant (rs80357596), also reported as 2798del4, has been described in several individuals with hereditary breast and ovarian syndrome (Azzollini 2016, Borg 2010, Couch 1997, Walsh 2011). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37481), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, 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 Azzollini J et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Couch F 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. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255129 SCV001747808 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659792 SCV001878017 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) RCV000031062 SCV000053657 pathogenic Breast-ovarian cancer, familial 1 2012-02-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031062 SCV000144509 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 RCV000047925 SCV000587245 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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