ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9924C>A (p.Tyr3308Ter) (rs4987049)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257043 SCV000328175 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000257043 SCV000324798 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000479392 SCV000572775 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9924C>A at the cDNA level and p.Tyr3308Ter (Y3308X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 111 amino acids are no longer translated causing loss of the NLS2 (Borg 2010). BRCA2 Tyr3308Ter due to an alternate nucleotide substitution (c.9924C>G) at the same position, has been observed in several individuals with Hereditary Breast and Ovarian Cancer (Naseem 2006, Alsop 2012). In addition, functional studies of this truncating variant, including assays measuring sensitivity to DNA damaging agents, homologous recombination, genomic instability and RAD51 focus formation all confirm the pathogenicity of this variant (Hucl 2008, Kuznetsov 2008). Based on currently available evidence, we consider this variant to be pathogenic.

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.