ClinVar Miner

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

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Total submissions: 12
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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) RCV000077479 SCV000282474 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000045914 SCV000073927 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the BRCA2 mRNA at codon 3308 (p.Tyr3308*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated BRCA2 protein. This variant is present in population databases (rs4987049, ExAC 0.003%). This variant has been reported in a family affected with breast and colorectal cancer (PMID: 17026620), and an individual affected with ovarian cancer (PMID: 22711857). It is also known as 10152C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52916). While the pathogenicity of truncating variants located in this last coding exon is not clinically conclusive due to the observation of neutral truncating variants (PMID: 8896551, 18097605, 20104584), the deleterious effect of this variant has been well established in cell-based model systems that show hypersensitivity to genotoxic damage, defective homologous recombination and RAD51-mediated DNA repair, and increased chromosomal aberrations in cells carrying this variant (PMID: 18593900, 18607349). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131045 SCV000185975 pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Deficient protein function in appropriate functional assay(s)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768644 SCV000219428 pathogenic Breast and/or ovarian cancer 2016-07-06 criteria provided, single submitter clinical testing
GeneDx RCV000221171 SCV000278890 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9924C>G 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>TAG), and is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay is not expected to occur, the protein truncation is significant since the last 111 amino acids are no longer translated, disrupting the NLS2 domain (Borg 2010). BRCA2 c.9924C>G, previously reported as BRCA2 10152C>G using alternate nomenclature, has been observed in several individuals with personal and/or family histories of breast or ovarian cancer (Krainer 1997, Naseem 2006, Waddell 2008, Alsop 2012). In addition, functional studies 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). This variant is considered pathogenic.
Color RCV000131045 SCV000292175 pathogenic Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077479 SCV000328176 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045914 SCV000695281 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 9924C>G (p.Tyr3308X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 2/121266 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It was reported in several HBOC patients indicating pathogenicity. Moreover, functional studies demonstrated the variant to result in defective in homologous recombination, compromised, radiation-induced RAD51 foci formation and elevated numbers of chromosomal aberrations further supporting a deleterious impact. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000077479 SCV000839932 pathogenic Breast-ovarian cancer, familial 2 2018-02-06 criteria provided, single submitter clinical testing A heterozygous c.9924C>G (p.Y3308*) pathogenic variant in the BRCA2 gene was detected in this individual. This variant has been previously described in multiple individuals with breast, colorectal, and ovarian cancer (PMID: 17026620, 22711857). In addition, functional studies have shown that the c.9924C>G (p.Y3308*) variant alters homologous recombination and increases chromosomal aberrations in cells (PMID: 18593900, 18607349). Therefore, we consider this variant to be pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077479 SCV000109277 pathogenic Breast-ovarian cancer, familial 2 2013-02-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077479 SCV000145730 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045914 SCV000588016 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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