ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.518delG (rs80359492)

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Total submissions: 12
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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) RCV000031530 SCV000300330 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 RCV000044599 SCV000072612 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly173Valfs*12) 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 an individual affected with breast cancer (PMID: 25452441). This variant is also known as c.517-1_517-1delG in the literature. ClinVar contains an entry for this variant (Variation ID: 37949). Experimental studies using a splicing minigene reporter assay have been reported for this variant with conflicting results (PMID: 23983145, 20215541). 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 RCV000222906 SCV000276042 pathogenic Hereditary cancer-predisposing syndrome 2017-12-07 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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031530 SCV000327162 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000483634 SCV000568448 pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.518delG at the cDNA level and p.Gly173ValfsX12 (G173VfsX12) at the protein level. The normal sequence, with the base that is deleted in brackets, is cagG[delG]TCGT, where the capital letters are exonic and lowercase are intronic. The deletion causes a frameshift which changes a Glycine to a Valine at codon 173, and creates a premature stop codon at position 12 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.518delG, published as 746delG using alternate nomenclature, has been observed in association with female and male breast cancer (Churpek 2015, Pritzlaff 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483634 SCV000600630 pathogenic not provided 2017-07-19 criteria provided, single submitter clinical testing
Counsyl RCV000031530 SCV000677665 pathogenic Breast-ovarian cancer, familial 2 2017-01-03 criteria provided, single submitter clinical testing
Color RCV000222906 SCV000683684 pathogenic Hereditary cancer-predisposing syndrome 2015-06-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044599 SCV000694838 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-08 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.518delG (p.Gly173ValfsX12) 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. The variant is located close to a canonical splice site therefore it could affect splicing. However, 5/5 computational tools predict no significant impact on normal splicing, which was confirmed by a minigene study (Di Giacomo 2013). Thus this frameshift variant is unlikely to be skipped through alternative splicing. The variant was absent in 246102 control chromosomes (gnomAD). The variant, c.518delG, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Lee 2008, Churpek 2014, Couch 2015, Pritzlaff 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031530 SCV000054135 pathogenic Breast-ovarian cancer, familial 2 2011-09-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031530 SCV000147059 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 RCV000044599 SCV000587555 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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