ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9501+3A>T (rs61757642)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131261 SCV000186226 likely benign Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),RNA Studies
Breast Cancer Information Core (BIC) (BRCA2) RCV000031825 SCV000147652 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131261 SCV000902673 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031825 SCV000744565 likely benign Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045838 SCV000592289 uncertain significance not specified 2015-09-25 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735627 SCV000863765 uncertain significance Breast and/or ovarian cancer 2013-08-23 no assertion criteria provided clinical testing
GeneDx RCV000656812 SCV000210508 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9501+3A>T or IVS25+3A>T and consists of an A>T nucleotide substitution at the +3 position of intron 25 of the BRCA2 gene. This variant, also known as 9729+3A>T using alternate nomenclature, has been observed in breast and/or ovarian cancer families (Capalbo 2006, Papi 2009, Borg 2010, Gabald? Barrios 2017). In vitro and in vivo RNA studies report that BRCA2 c.9501+3A>T results in skipping of exon 25 (Bonnet 2008, Papi 2009, Borg 2010, Whiley 2011). In addition, the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Splicing Working Group concluded that BRCA2 c.9501+3A>T produces unequivocal splicing aberrations (Whiley 2014). However, a minigene splicing assay quantified the aberrant splicing and found that this variant results in less than 15% aberrant transcript, meaning that the full length transcript is predominant (Acedo 2015). Additionally, the adenine (A) nucleotide that is altered is not conserved. BRCA2 c.9501+3A>T was observed at an allele frequency of 0.02% (16/66,618) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Despite BRCA2 c.9501+3A>T being proven to result in skipping of exon 25, we are unable to predict the clinical impact of this variant given that the normal transcript appears to be more abundant. Thus, we consider it to be a variant of uncertain significance.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031825 SCV000743367 likely benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Hereditary Cancer Genetics group,Vall d'Hebron Institute of Oncology RCV000167798 SCV000916375 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-03-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000045838 SCV000918821 uncertain significance not specified 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9501+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Five of five splice prediction tools predict the weakening, but not abolishment of the 5' donor site due to the variant, which are supported by multiple functional studies that showed exon 25 may be skipped. However, several of these studies found that only a small fraction of transcript skipped exon 25, thereby calling into question the clinical relevance of the variant (Acedo_2014). The variant allele was found at a frequency of 0.00011 in 276820 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00011 vs 0.00075), allowing no conclusion about variant significance. The c.9501+3A>T variant has been reported in the literature in individuals affected with HBOC. However, these report(s) do not provide supporting data (e.g., cosegregation data) and thus unequivocal conclusions about the association of the variant with HBOC is unclear. In addition, co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5796_5797delTA/p.His1932GlnfsX12; BRCA2 c.2957dup/p.Asn986LysfsX2; BRCA1 c.1266T>G/p.Tyr422X), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with conflicting interpretations, including benign and uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS-possibly benign.
Invitae RCV000167798 SCV000073851 benign Hereditary breast and ovarian cancer syndrome 2017-12-30 criteria provided, single submitter clinical testing
Laboratoire de Biologie et Génétique du Cancer,Centre François Baclesse RCV000031825 SCV000538194 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mendelics RCV000167798 SCV000838906 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031825 SCV000196027 uncertain significance Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045838 SCV000296748 uncertain significance not specified 2017-07-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031825 SCV000054433 benign Breast-ovarian cancer, familial 2 2011-09-16 no assertion criteria provided clinical testing

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