ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5576_5579del (p.Ile1859fs) (rs80359520)

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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) RCV000031556 SCV000282408 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044684 SCV000072697 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile1859Lysfs*3) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs770318608, ExAC 0.02%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 23633455, 8705994, 22160602, 22217648, 23683081). This variant is also known as 5803delATTA, 5804del4, and 5574_5577delAATT in the literature. ClinVar contains an entry for this variant (Variation ID: 37975). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131118 SCV000186048 pathogenic Hereditary cancer-predisposing syndrome 2017-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000160296 SCV000210767 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.5576_5579delTTAA at the cDNA level and p.Ile1859LysfsX3 (I1859KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAA[delTTAA]AAAAG. This deletion, also known as 5802del4 or 5804del4 using alternate nomenclature, causes a frameshift, which changes an Isoleucine to a Lysine at codon 1859, and creates a premature stop codon at position 3 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. BRCA2 c.5576_5579delTTAA has been reported as a recurrent pathogenic variant in breast and/or ovarian cancer families and is suggested to be a pathogenic founder variant in Asian populations (Ikeda 2001, Sugano 2008, Wang 2012, Kang 2015, Kim 2016, Eoh 2017, Pritzlaff 2017). We consider this variant to be pathogenic.
Color RCV000131118 SCV000292136 pathogenic Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160296 SCV000296678 pathogenic not provided 2019-05-17 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 found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031556 SCV000327232 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000031556 SCV000577957 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044684 SCV000588101 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044684 SCV000591975 pathogenic Hereditary breast and ovarian cancer syndrome 2014-08-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160296 SCV000602738 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing The BRCA2 c.5576_5579delTTAA;p.Ile1859fs variant (also known as 5802del and 5803del) has been described in the literature in individuals and families with breast and ovarian cancer (Foster 1996, George 2013, Schneegans 2012). The variant is listed in the dbSNP variant database (rs80359521) but is not listed in the general population-based databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). This variant deletes four nucleotides and creates a frameshift, which is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. References: Foster KA et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996 56(16):3622-5. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 19(13):3474-84. Schneegans SM et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 11(2):181-8.
Department of Medical Genetics,Oslo University Hospital RCV000031556 SCV000605703 pathogenic Breast-ovarian cancer, familial 2 2017-01-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000044684 SCV000605790 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-28 criteria provided, single submitter clinical testing The p.Ile1859fs variant in BRCA2 has been reported in >35 individuals with BRCA2 -associated cancers (Saghir 2015, Kim 2016, Breast Cancer Information Core datab ase). It has also been identified in 2/10144 African chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359520); h owever, this frequency is low enough to be consistent with the frequency of here ditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 1859 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. In addition, this variant was classified as Pathogen ic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000 282408.1). In summary, this variant meets our criteria to be classified as patho genic for HBOC in an autosomal dominant manner.
Counsyl RCV000031556 SCV000677685 pathogenic Breast-ovarian cancer, familial 2 2015-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044684 SCV000694882 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.5576_5579delTTAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.5585_5588delTGAA, c.5603_5606delACAG, c.5616_5620delAGTAA). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.003% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been cited in numerous affected individuals via the literature and databases, and has been classified by multiple reputable databases and clinical labs as "pathogenic". Taken together, this variant has been classified as as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000160296 SCV000805726 pathogenic not provided 2017-12-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031556 SCV000054161 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031556 SCV000146636 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044684 SCV000587774 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
GenomeConnect, ClinGen RCV000509336 SCV000607032 not provided Fanconi anemia, complementation group D1; Hereditary breast and ovarian cancer syndrome no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735566 SCV000863704 pathogenic Breast and/or ovarian cancer 2009-03-10 no assertion criteria provided clinical testing

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