ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.517-2A>G (rs81002858)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162897 SCV000213384 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Breast Cancer Information Core (BIC) (BRCA2) RCV000077347 SCV000147050 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000162897 SCV000904690 pathogenic Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077347 SCV000327158 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077347 SCV000677664 pathogenic Breast-ovarian cancer, familial 2 2017-05-01 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077347 SCV000605706 pathogenic Breast-ovarian cancer, familial 2 2017-01-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044589 SCV000591692 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
GeneDx RCV000221055 SCV000279588 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.517-2A>G or IVS6-2A>G and consists of a A>G nucleotide substitution at the -2 position of intron 6 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 745-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Consistent with splicing predictions, Houdayer et al. (2012) studied this variant in a PAXgene assay and observed complete skipping of exon 7. Furthermore, this variant has been observed in individuals diagnosed with ovarian, early-onset breast, or aggressive prostate cancer (Jakubowska 2003, Song 2014, Eccles 2016, Plaskocinska 2016, Pritchard 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044589 SCV000694836 pathogenic Hereditary breast and ovarian cancer syndrome 2016-11-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.517-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict significant impact on normal splicing, and these predictions have been confirmed by functional studies. This variant is absent in 124020 control chromosomes. This variant has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044589 SCV000072602 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast or ovarian cancer (PMID: 14647210, 24728189, 26681682, 27836010). ClinVar contains an entry for this variant (Variation ID: 51801). Experimental studies have shown that this variant causes abnormal splicing which creates a transcript that is lacking of exon 7 and results in a frameshift protein (PMID: 22505045). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044589 SCV000605808 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-23 criteria provided, single submitter clinical testing The c.517-2A>G variant in BRCA2 has been reported in at least 6 individuals with BRCA2-associated cancers (Jakubowska 2003, Breast Cancer Information Core (BIC) database) and was absent from large population studies. In vitro functional stu dies provide some evidence that the c.517-2A>G variant may impact protein functi on (Houdayer 2012). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBO C). In summary, this variant meets criteria to be classified as pathogenic for H BOC in an autosomal dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221055 SCV000887844 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044589 SCV000587554 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077347 SCV000109144 likely pathogenic Breast-ovarian cancer, familial 2 2011-01-06 no assertion criteria provided clinical testing

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