ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8954-3C>G (rs81002844)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000114023 SCV000786601 uncertain significance Breast-ovarian cancer, familial 2 2018-06-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV001018542 SCV001179794 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing The c.8954-3C>G intronic variant (also known as IVS22-3C>G) results from a C to G substitution 3 nucleotides upstream from coding exon 23 of the BRCA2 gene. This alteration was identified once in a validation cohort for a BRCA1 and BRCA2 next-generation sequencing panel study (Trujillano D et al. J Mol Diagn, 2015 Mar;17:162-70). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site and in a functional splicing assay, this alteration resulted in the out-of-frame insertion of 2 nucleotides in exon 23 of BRCA2 (Acedo A et al. Breast Cancer Res., 2012 May;14:R87). Another nearby alteration, c.8954-5A>G, has been classified as likely pathogenic based on segregation with disease in one family and on RT-PCR analysis demonstrating that this alteration results in out-of-frame retention of 4 nucleotides of intron 22 and in a truncated mRNA transcript (Santos C et al. J Mol Diagn, 2014 May;16:324-34; Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92; de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7). This nucleotide position is poorly conserved in available vertebrate species. Alterations that cause aberrant splicing are expected to result in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Color Health, Inc RCV001018542 SCV001348396 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing
Invitae RCV001366157 SCV001562452 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-28 criteria provided, single submitter clinical testing This sequence change falls in intron 22 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual who underwent genetic testing for hereditary breast and ovarian cancer (PMID: 25556971). ClinVar contains an entry for this variant (Variation ID: 52712). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change produces an abnormally spliced mRNA transcript that is predicted to result in a truncated protein (PMID: 22632462, 24123850). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114023 SCV000147500 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 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.