ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8755-1G>A (rs81002812)

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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 RCV000131043 SCV000185973 pathogenic Hereditary cancer-predisposing syndrome 2017-09-29 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,Functionally-validated splicing mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000031766 SCV000147452 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000131043 SCV000906954 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031766 SCV000327961 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031766 SCV000220669 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-03 criteria provided, single submitter literature only
Division Human Genetics,Medical University Innsbruck RCV000031766 SCV000212032 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031766 SCV000282251 uncertain significance Breast-ovarian cancer, familial 2 2016-04-15 reviewed by expert panel curation Insufficient evidence to determine clinical significance. Variant allele produces r.8755_8953del, r.8755_9004del AND full-length transcripts.
GeneKor MSA RCV000238986 SCV000296836 likely pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000220836 SCV000918928 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8755-1G>A variant involves the alteration of a conserved intronic nucleotide and 3/5 splice prediction tools predict a significant impact on normal splicing. A functional study, Colombo_2013, shows the variant to produce two aberrant transcripts, skipping of exon 22 (resulting in p.Gly2919LeufsX3) and skipping of exon 22 + 51 bp at the 5' end of exon 23 (resulting in p.Gly2919LysfsX26). This variant is absent in 244786 control chromosomes (gnomAD). A publication, Tea_2014, reports the variant in 26 affected individuals from 13 families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "Pathogenic." Taken together, this variant is classified as pathogenic.
Invitae RCV000220836 SCV000073632 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 21 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 many families with a history of breast and/or ovarian cancer (PMID: 24156927, 18489799), and observed to segregate with disease in two families (PMID: 9971877). ClinVar contains an entry for this variant (Variation ID: 38183) Experimental studies have shown that this variant disrupts splicing of exon 22 (PMID: 9971877, 23451180, 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220836 SCV000271337 pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-01 criteria provided, single submitter clinical testing The c.8755-1G>A variant in BRCA2 has been reported in at least 10 individuals with BRCA2-associated cancers and segregated with disease in 3 affected relatives from 3 families (Wagner 1999, Machackova 2008, Breast Cancer Information Core database, www.research.nhgri.nih.gov/bic/). It was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and in vitro studies indicate that this variant results in skipping of exon 22, leading to a premature stop codon and an abnormal or absent protein (Machackova 2008, Colombo 2013). Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein, segregation studies, and prevalence in affected individuals.
Mendelics RCV000220836 SCV000838885 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000220836 SCV000587969 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031766 SCV000054374 likely pathogenic Breast-ovarian cancer, familial 2 2011-04-18 no assertion criteria provided clinical testing

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