ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7976+5G>A (rs786201180)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162937 SCV000213424 pathogenic Hereditary cancer-predisposing syndrome 2020-01-24 criteria provided, single submitter clinical testing The c.7976+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 16 in the BRCA2 gene. This alteration has been identified in several Asian cohorts being tested for BRCA1 and BRCA2 mutations (Bhaskaran SP et al. Int. J. Cancer, 2019 Aug;145:962-973; Wong MS et al. Mol. Cell, 2018 09;71:1012-1026.e3; Kwong A et al. J Mol Diagn, 2016 07;18:580-94; Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23). <span style="background-color:initial">This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site, however, this alteration demonstrated skipping of coding exon 16 (also called exon 17 in the literature) (Ambry internal data; Wong MS et al. Mol. Cell, 2018 09;71:1012-1026.e3). A close match alteration at the same nucleotide position, BRCA2 c.7976+5G>T was shown to produce the same splice defect in multiple unrelated carriers tested at different Spanish institutions (Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160). Based on the majority of evidence available to date, this alteration is considered a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258212 SCV000327778 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586885 SCV000695111 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7976+5G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 4/5 Alamut algorithms predict no significant change to normal splicing. In a published thesis by Kwong (2013), the variant was indicated to induce exon 17 skipping, similar to BRCA2 c.7976+5G>T. BRCA2 c.7976+5G>T has been reported to have a similar splicing pattern to WT, with full-length and 17,18 BRCA2 transcripts detected at similar levels (PMID:24123850). Since BRCA2 exon 17 skipping can be seen in both WT and variants at this particular intronic nucleotide position, it is unclear what the significance, if any, this exon 17 skipping has. This variant has been cited in one breast cancer patient (thesis of Kwong, 2013) without evidence of causality (i.e. co-segregation studies). This variant was absent in 121150 control chromosomes. Additionally, one clinical diagnostic laboratory classified the variant as a VUS, and one reputable databases listed the variant to be of clinical importance without providing evidence to independently evaluate. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000637349 SCV000758802 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 26187060). This variant is also known as IVS17+5G>A. ClinVar contains an entry for this variant (Variation ID: 183947). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with skipping of exon 17 but is expected to preserve the integrity of the reading frame (PMID: 30174293). This variant disrupts the c.7976+5G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 29969168). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000258212 SCV000786313 uncertain significance Breast-ovarian cancer, familial 2 2018-04-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586885 SCV000889144 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162937 SCV000906566 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-26 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496302 SCV000587924 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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