ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8953+1G>T (rs81002882)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131051 SCV000185981 pathogenic Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Breast Cancer Information Core (BIC) (BRCA2) RCV000031781 SCV000147497 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131051 SCV000689161 pathogenic Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031781 SCV000328007 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031781 SCV000677703 pathogenic Breast-ovarian cancer, familial 2 2017-01-03 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031781 SCV000244490 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
GeneDx RCV000254648 SCV000108642 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8953+1G>T or IVS22+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 22 of the BRCA2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. RT-PCR and minigene studies have shown that this variant resulted in multiple aberrant transcripts, with skipping of exon 22 being the most prevalent (Whiley 2011, Acedo 2015). Also reported as BRCA2 9181+1G>T using alternate nomenclature, this variant has been observed in individuals with early-onset or bilateral breast cancer as well as in Hereditary Breast and Ovarian Cancer families (Borg 2010, Whiley 2011, Sharma 2016, Roed Nielsen 2016). Based on currently available evidence, we consider BRCA2 c.8953+1G>T to be pathogenic.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131051 SCV000747806 pathogenic Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000213611 SCV000918931 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8953+1G>T variant involves the alteration of a conserved intronic nucleotide located at the intron-exon boundary. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. These predictions have been confirmed by functional studies that showed variant lead to exon 22 skipping (Whiley_2011 and Acedo_2014). This variant is absent in 242946 control chromosomes. It has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000213611 SCV000271338 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The c.8953+1G>T variant in BRCA2 has been reported in 3 individuals with BRCA2-a ssociated cancers (Borg 2010, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alte red splicing leading to an abnormal or absent protein. In vitro functional studi es provide some evidence that the c.8953+1G>T variant impacts splicing (Whiley 2 011, Acedo 2015). Heterozygous loss of function of the BRCA2 gene is an establis hed disease mechanism in individuals with hereditary breast and ovarian cancer ( HBOC). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000244490.1). In summar y, the c.8953+1G>T variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, function al evidence, and the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254648 SCV000887949 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000213611 SCV000587980 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031781 SCV000054389 pathogenic Breast-ovarian cancer, familial 2 2012-02-21 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.