ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8487+1G>A (rs81002798)

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Total submissions: 14
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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) RCV000077441 SCV000244485 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Invitae RCV000220501 SCV000073547 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 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 reported in families and individuals affected with breast and/or ovarian cancer (PMID: 12606139, 16619214, 24156927, 17591842). It is also known as IVS19+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 52602). Based on multifactorial likelihood algorithms using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134, 25085752). Experimental studies have shown that this variant leads to the skipping of exon 19, resulting in an in-frame deletion of 52 amino acids within the essential DNA-binding domain (DBD) of the BRCA2 protein (PMID: 12606139, 16619214, 22632462) 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.
Ambry Genetics RCV000131086 SCV000186016 pathogenic Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000212276 SCV000210473 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8487+1G>A or IVS19+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 19 of the BRCA2 gene. Splicing assays have demonstrated that this variant, also defined as BRCA2 8715+1G>A using alternate nomenclature, results in skipping of exon 19 (Agata 2003, Chen 2006, Acedo 2012). This disruption would be predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Agata 2003, Chen 2006, Veschi 2007, Tea 2014). BRCA2 c.8487+1G>A was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, and/or family studies. Based on the current evidence, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220501 SCV000271334 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The c.8487+1G>A variant in BRCA2 has been reported in at least 9 individuals wit h BRCA2-associated cancers (Chen 2006, Veschi 2007,Breast Cancer Information Cor e (BIC) database), and was absent from large population studies. This variant oc curs in the invariant region (+/- 1,2) of the splice consensus sequence and is p redicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide evidence that the c.8487+1G>A variant impacts s plicing (Agata 2003, Acedo 2012, Chen 2006). Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HB OC). Furthermore, this variant was classified as Pathogenic on August 10, 2015 b y the ClinGen-approved ENIGMA expert panel (ClinVar SCV000244485.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner based upon absence from controls, functional evidence, and predicted impact to the protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077441 SCV000327903 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000131086 SCV000689129 pathogenic Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000077441 SCV000786232 pathogenic Breast-ovarian cancer, familial 2 2018-03-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212276 SCV000887943 pathogenic not provided 2016-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000220501 SCV000918865 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8487+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence supporting these predictions, which causes skipping of exon 19 leading to an abnormal protein product (p.Ille2778_Gln2829del)(Chen_2006, Agata_2003). The variant was absent in 276832 control chromosomes. c.8487+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, indicating the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ITMI RCV000122367 SCV000083918 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077441 SCV000109239 pathogenic Breast-ovarian cancer, familial 2 2012-11-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077441 SCV000147377 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000220501 SCV000587957 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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