ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9501+3A>T (rs61757642)

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Total submissions: 22
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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) RCV000031825 SCV001161629 benign Breast-ovarian cancer, familial 2 2019-06-18 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 1 based on posterior probability = 4.85E-07
Invitae RCV000167798 SCV000073851 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131261 SCV000186226 likely benign Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);RNA Studies
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
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656812 SCV000296748 uncertain significance not provided 2020-01-17 criteria provided, single submitter clinical testing
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
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
Mendelics RCV000167798 SCV000838906 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131261 SCV000902673 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing This variant causes an A>T nucleotide substitution at the +3 position of intron 25 of the BRCA2 gene. This variant is also known as IVS25+3A>T by Breast Cancer Information Core (BIC) nomenclature. RNA studies have reported exon 25 skipping in 10 - 20% of the transcript in cells from individuals who carry this variant (PMID: 18424508, 18821011, 20104584, 21394826, 22505045, 24212087, 28905878, 30101128, 31343793). To our knowledge, functional protein studies have not been performed for this variant. This variant has been reported in families and individuals affected with breast and/or ovarian cancer (PMID: 16760289, 18821011, 20104584, 22505045, 28477318, 29884136). This variant has also been identified in 31/282458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045838 SCV000918821 likely benign not specified 2021-05-10 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. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens but does not abolish the canonical 5' donor site. These predictions are supported by multiple functional studies that showed exon 25 was 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 (example, Acedo_2014). In further contrast, a recently published study evaluating RNA genetic testing to re-classify splice variants has reported that this variant has no impact on splicing in accordance with the ACMG BS3 gudeline specification supporting its re-classification as likely benign (Karam_2019). The variant allele was found at a frequency of 0.00012 in 251052 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.00075), allowing no conclusion about variant significance. c.9501+3A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the UMD database and also observed in our laboratory and the literature (examples, UMD-BRCA2 c.5796_5797delTA, p.His1932GlnfsX12; BRCA2 c.2957dup, p.Asn986LysfsX2; BRCA1 c.1266T>G, p.Tyr422X; our laboratory-BRCA1 c.5153-2del; Karam_2019, an unspecified observation in trans with a pathogenic mutation in an individual without biallelic disease), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=9). Among these, the expert panel settled on a classification as benign. Some submitters cite overlapping but not all evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Mendelics RCV000031825 SCV001139264 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656812 SCV001249504 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031825 SCV001267537 uncertain significance Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286784 SCV001473401 uncertain significance none provided 2020-01-11 criteria provided, single submitter clinical testing The BRCA2 c.9501+3A>T variant (rs61757642) is reported in the literature in individuals and families affected with breast and/or ovarian cancer (Bonnet 2008, Borg 2010, Papi 2009). This variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (24/128878 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Indeed, RNA and minigene analyses show that this variant leads to skipping of exon 25; however, this occurs in only a small subset of transcripts, and it is unclear if this limited effect is clinically significant (Acedo 2015, Bonnet 2008, Davy 2017, Whiley 2011). Due to limited information, the clinical significance of the c.9501+3A>T variant is uncertain at this time. References: Acedo A et al. Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. Hum Mutat. 2015 Feb;36(2):210-21. Bonnet C et al. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet. 2008 Jul;45(7):438-46. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Davy G et al. Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer. Eur J Hum Genet. 2017 Oct;25(10):1147-1154. Papi L et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. 2009 Oct;117(3):497-504. Whiley PJ et al. Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. Hum Mutat. 2011 Jun;32(6):678-87.
Mayo Clinic Laboratories, Mayo Clinic RCV000656812 SCV001714442 uncertain significance not provided 2019-08-17 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000031825 SCV000147652 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656812 SCV000592289 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 c.9501+3A>T variant was identified in 3 of 4414 proband chromosomes (frequency: 0.001) from individuals or families with breast/ovarian cancers in 2 studies (Borg 2010, Papi 2009). Giannini et al. (2006) also identified the variant in an Italian cohort of breast/ovarian cancer families, frequency unspecified. Multiple functional assays using minigene reporters and/or RNA analysis have shown that the variant causes incomplete skipping of exon 25, with wildtype transcript present and the splicing alteration affecting only a fraction of the transcripts from the variant allele (Bonnet 2008, Whiley 2011, Acedo 2015, Houdayer 2012). The variant was also identified in dbSNP (ID: rs61757642) “With likely pathogenic allele”, in the Exome Variant Server project in 3 of 8600 European American alleles (frequency: 0.0003), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 18 of 121142 chromosomes (frequency: 0.0001) (or 16 individuals from a population of European (Non-Finnish) individuals and 2 individuals from a population of Latinos). It was also identified by our laboratory in 7 individuals with breast and ovarian cancer co-occuring with BRCA2 c.9976A>T in at least 3 individuals. The variant was identified in the Clinvitae database (4x), ARUP Laboratories BRCA Mutations Database (classification pathogenic), the ClinVar database with conflicting interpretations (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as likely pathogenic by GeneDX and CHEO, and uncertain significance by Ambry Genetics, BIC and Invitae), GeneInsight COGR database (2x, classified as “likely pathogenic” and unclassified), the BIC database (15x with unknown clinical importance and pending classification), UMD (classified as likely casual 15x, including 1x co-occuring with a pathogenic mutation c.5796_5797delTA (p.His1932GlnfsX12)). The c.9501+3A>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
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
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

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