ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2330dup (p.Asp777fs) (rs80359328)

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Total submissions: 18
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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) RCV000077683 SCV000300509 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077683 SCV000195969 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000160270 SCV000210721 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.2330dupA at the cDNA level and p.Asp777GlufsX11 (D777EfsX11) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AAGG[dupA]TGTT. The duplication causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 777, and creates a premature stop codon at position 11 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.2330dupA, previously reported as 2558insA using alternate nomenclature, has been observed in association with breast, ovarian, prostate, and pancreatic cancer (Al-Saffer 2002, Edwards 2010, Song 2014, George 2017, Lowery 2018). We therefore consider this variant to be pathogenic.
Ambry Genetics RCV000163933 SCV000214529 pathogenic Hereditary cancer-predisposing syndrome 2017-06-20 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)
Invitae RCV000206474 SCV000259811 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp777Glufs*11) in the BRCA2 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 the literature in individuals with prostate cancer (PMID: 12474142), fallopian tube carcinoma (PMID: 11812938), and ovarian cancer (PMID: 24728189, 12414830). This variant is also known as 2558insA in the literature. ClinVar contains an entry for this variant (Variation ID: 91775). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160270 SCV000296622 pathogenic not provided 2015-09-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077683 SCV000326691 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000206474 SCV000588083 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 RCV000206474 SCV000591801 pathogenic Hereditary breast and ovarian cancer syndrome 2014-04-23 criteria provided, single submitter clinical testing
Counsyl RCV000077683 SCV000677671 pathogenic Breast-ovarian cancer, familial 2 2017-04-14 criteria provided, single submitter clinical testing
Color RCV000163933 SCV000683480 pathogenic Hereditary cancer-predisposing syndrome 2015-06-11 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735532 SCV000902194 pathogenic Breast and/or ovarian cancer 2017-07-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000206474 SCV000919031 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2330dupA (p.Asp777GlufsX11) 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 (eg. c.2368G>T/p.Glu790X, c.2400_2401delTA/p.Asn801fsX3). The variant allele was found at a frequency of 8e-06 in 248882 control chromosomes (gnomAD and publication data). c.2330dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other tumor phenotypes. 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 (Edwards_2003, Oros_2004, Alsop_2012, Song_2014, George_2016). Nine 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.
OMIM RCV000009928 SCV000030149 pathogenic Malignant tumor of prostate 2003-01-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000077683 SCV000109486 pathogenic Breast-ovarian cancer, familial 2 2011-12-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077683 SCV000146031 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 RCV000206474 SCV000587629 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 RCV000735532 SCV000863670 pathogenic Breast and/or ovarian cancer 2015-10-28 no assertion criteria provided clinical testing

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