ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7008-2A>T (rs81002823)

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Total submissions: 10
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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) RCV000113689 SCV000282248 pathogenic Breast-ovarian cancer, familial 2 2016-04-03 reviewed by expert panel curation Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7008_7435del, r.7008_7017del, and r.7008_7253del transcripts (encoding predicted non-functional proteins).
Ambry Genetics RCV000220759 SCV000275758 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation
GeneDx RCV000235662 SCV000293482 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7008-2A>T or IVS13-2A>T and consists of an A>T nucleotide substitution at the -2 position of intron 13 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7236-2A>T. This variant destroys a canonical splice acceptor 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. This variant has been published, in both RT-PCR analyses of RNA and a PAXgene assay, to result in aberrant splicing (Pensabene 2009, Colombo 2009, Colombo 2013, Houdayer 2012). Based on the current evidence, we consider this variant to be pathogenic. BRCA2 c.631G>A and BRCA2 c.7008-2A>T have been published to co-occur in several probands with histories of breast, ovarian, and/or pancreatic cancer, absent of Fanconi Anemia, and are likely in cis (Pensabene 2009, Colombo 2009, Lowery 2011, Gaildrat 2012). Both of these variants are predicted to cause aberrant splicing and result in an out of frame deletion of an exon and either premature protein truncation or nonsense-mediated mRNA decay. Therefore, this allele, which likely carries both variants in cis is considered pathogenic. Of note, as these two variants are likely in cis, we would not expected this individual to have Fanconi Anemia.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113689 SCV000327577 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504523 SCV000592089 pathogenic Hereditary breast and ovarian cancer syndrome 2013-03-14 criteria provided, single submitter clinical testing
Counsyl RCV000113689 SCV000677696 likely pathogenic Breast-ovarian cancer, familial 2 2016-12-05 criteria provided, single submitter clinical testing
Color RCV000220759 SCV000683841 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000504523 SCV000695025 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7008-2A>T variant is located at a conserved position, known to affect splicing, with 5/5 splice prediction tools predicting a significant impact on splicing, which is further supported by multiple functional studies. A functional study, Colombo_2009, indicates the variant tocause a "leaky" effect on splicing, allowing the expression from the mutant allele of a transcript lacking both exons 7 and 14 (delta7, delta14) and a transcript lacking exon 7 only (delta7). The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP). Multiple publications cite the variant in affected individuals, predominantly, to co-occur with another pathogenic BRCA2 variant, c.631G>A. However, it remains unclear whether these variants were consistently observed in cis or trans. Multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113689 SCV000146998 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735596 SCV000863734 pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing

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