ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8488-1G>A (rs397507404)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213906 SCV000278235 pathogenic Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV000213906 SCV000683971 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031747 SCV000327907 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031747 SCV000677712 pathogenic Breast-ovarian cancer, familial 2 2015-03-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763329 SCV000894006 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000160152 SCV000210474 likely pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8488-1G>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 reported as BRCA2 8716-1G>A using alternate nomenclature, results in skipping of exon 20 (Acedo 2012, Santos 2014, Acedo 2015). 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. However, these studies have detected several additional in-frame and out-of-frame transcripts (Howlett 2002, Acedo 2012, Santos 2014, Acedo 2015). Functional studies performed by Stoepker et. al. (2015) demonstrated that this variant showed only marginal sensitivity to PARP inhibitor and other DNA damaging agents and wild type levels of RAD51 foci formation. This variant has been observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Acedo 2012, Kim 2012, Santos 2014, Peixoto 2015, Fernandes 2016, Shin 2016, Park 2018), but has also been observed in an unaffected control patient (Naslavsky 2017). This variant was reported in the homozygous state in an individual with Fanconi anemia; however, the phenotype of this patient was classified as mild (Howlett 2002). Based on the currently available evidence, we consider BRCA2 c.8488-1G>A to be a likely pathogenic variant.
Gharavi Laboratory,Columbia University RCV000160152 SCV000809442 pathogenic not provided 2018-09-16 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031747 SCV000584075 pathogenic Breast-ovarian cancer, familial 2 2016-02-11 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000231355 SCV000916934 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8488-1G>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: Three predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Acedo_2012, Santos_2014). The variant was absent in 246164 control chromosomes (gnomAD and publications). The variant, c.8488-1G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease (Acedo_2012, Kim_2012, Peixoto_2014, Frenandes_2016). Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.470_471delCT, p.Ser157X). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000231355 SCV000283345 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 19 of the BRCA2 gene. It is expected to disrupt mRNA 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 the literature in individuals affected with breast cancer (PMID: 22632462, 24607278, 27741520) and Fanconi anemia (PMID: 24301060). This variant is also known as Ex19-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38164). Experimental studies have shown that this variant alters RNA splicing, but the clinical significance of these findings is uncertain (PMID: 22632462, 24607278, 25382762). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics RCV000231355 SCV000838877 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000009920 SCV000030141 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160152 SCV000600809 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000231355 SCV000587958 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031747 SCV000054354 likely pathogenic Breast-ovarian cancer, familial 2 2011-09-23 no assertion criteria provided clinical testing

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