ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9925G>T (p.Glu3309Ter) (rs80359251)

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Total submissions: 7
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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) RCV000112825 SCV000301420 uncertain significance Breast-ovarian cancer, familial 2 2019-06-05 reviewed by expert panel curation Premature stop codon is located between the recognised high-risk truncating variant c.9924C>G (p.Tyr3308Ter) and the known low-risk truncating variant c.9976A>T (p.Lys3326Ter). Functional assay result similar to (Likely) Benign variants - Complementation of cell lethal phenotype and homology directed repair activity approximately 75% of wild-type construct (Mesman 2019).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112825 SCV000328177 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000112825 SCV000677709 likely pathogenic Breast-ovarian cancer, familial 2 2017-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000657637 SCV000779381 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9925G>T at the cDNA level and p.Glu3309Ter (E3309X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been observed in at least one individual with ovarian cancer and was associated with reduced protein function (Kuznetsov 2008). Although results of cell survival/viability assays in mouse embryonic stem (ES) cells are conflicting, this variant consistently demonstrates hypersensitivity to DNA damaging agents and was shown to have reduced homology-directed repair activity when compared to wildtype (Kuznetsov 2008, Mesman 2018). Based on currently available evidence, we consider this variant to be pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112825 SCV000145733 pathogenic Breast-ovarian cancer, familial 2 1999-04-12 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496671 SCV000588017 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735634 SCV000863772 likely pathogenic Breast and/or ovarian cancer 2003-10-03 no assertion criteria provided clinical testing

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