ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8533_8534AG[2] (p.Glu2846fs) (rs80359714)

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Total submissions: 19
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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) RCV000009915 SCV000301287 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000045550 SCV000073563 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu2846Glyfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359714, ExAC 0.001%). This variant is clearly defined as a breast and/or ovarian cancer causative allele (PMID: 8673090, 21324516, 22401979). It is a common cause of cancer in individuals of French Canadian (PMID: 15382066, 9792861, 27603373), Yemenite Jewish (PMID: 9634522, 11512557), and Northern Sardinian (PMID: 19619314, 17640379) ancestry. This variant is also known as 8765delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 9328). 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 RCV000131085 SCV000186015 pathogenic Hereditary cancer-predisposing syndrome 2017-12-01 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 RCV000160308 SCV000210795 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.8537_8538delAG at the cDNA level and p.Glu2846GlyfsX22 (E2846GfsX22) at the protein level. This deletion is also known as BRCA2 c.8535delAG or 8765delAG using alternate nomenclature. The normal sequence, with the bases that are deleted in brackets, is AGAG[delAG]GAAG. The deletion causes a frameshift, changing a Glutamic Acid to a Glycine at codon 2846, and creating a premature stop codon at position 22 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.8537_8538delAG has been reported as a common pathogenic variant associated with hereditary breast/ovarian cancer in the French Canadian, Sardinian, and Czech populations (Foretova 2010, Janavicius 2010, Ghadirian 2014). We consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735482 SCV000219410 pathogenic Breast and/or ovarian cancer 2017-09-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045550 SCV000271336 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Glu2846fs variant in BRCA2 is a well-established pathogenic founder varian t for several populations, including French Canadians, Jewish-Yemenites, and Nor thern Sardinian (Tonin 1998, Lerer 1998, Ferla 2007). This variant has been ide ntified in 1/66688 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs80359716). This frequency is low enou gh to be consistent with the frequency of hereditary breast and ovarian cancer ( HBOC) in the general population. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 2846 and leads to a premature termination codon 22 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in HBOC. In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosom al dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160308 SCV000296650 pathogenic not provided 2015-07-14 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000009915 SCV000327919 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000009915 SCV000489211 pathogenic Breast-ovarian cancer, familial 2 2016-09-16 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045550 SCV000588121 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 RCV000045550 SCV000592208 pathogenic Hereditary breast and ovarian cancer syndrome 2013-11-14 criteria provided, single submitter clinical testing
Color RCV000131085 SCV000683979 pathogenic Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045550 SCV000916958 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8537_8538delAG (p.Glu2846GlyfsX22) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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., c.8546delA [p.Lys2849fsX14] and c.8575delC [p.Gln2859fsX4]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/245884 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in many HBOC patients and families, including 76 patients from the BIC database. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000009915 SCV000030136 pathogenic Breast-ovarian cancer, familial 2 1998-07-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000009915 SCV000054357 pathogenic Breast-ovarian cancer, familial 2 2013-04-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000009915 SCV000147396 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000009915 SCV000189901 pathogenic Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045550 SCV000587959 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 RCV000735482 SCV000863619 pathogenic Breast and/or ovarian cancer 2016-05-11 no assertion criteria provided clinical testing

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