ClinVar Miner

Submissions for variant NM_000059.3(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 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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
Integrated Genetics/Laboratory Corporation of America 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 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-27 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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 RCV000162937 SCV000906566 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-27 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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