ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8754+4A>T (rs81002893)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204178 SCV000260834 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change falls in intron 21 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: 220353). 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.8754+4A>G) has been determined to be pathogenic (PMID: 17011978, 27433846, 20927582, 17924331, 21990134, 17011978, 22505045). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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 RCV000410920 SCV000489241 uncertain significance Breast-ovarian cancer, familial 2 2016-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572423 SCV000665964 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-17 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Other data supporting pathogenic classification;RNA Studies;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000590686 SCV000695179 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8754+4A>T variant involves the alteration of a conserved nucleotide within the consensus splice site of intron 21. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict significant impact on normal splicing; in addition RESCUE-ESE predicts that the variant may affect an exonic splicing regulatory element. However, these predictions have yet to be confirmed by functional studies. Variant involving the same nucleotide (c.8754+4A>G) has been reported in affected individuals and classified as pathogenic by our lab. Nucleotide changes near the position for the variant of interest may also give rise to aberrant transcripts, and were found in HBOC patients with family history, e.g. c.8754+3G>C and c.8754+5G>A (Brandao_2011). These data suggest that the BRCA2 c.8754+4A>T variant is located within a highly conserved consensus splice site that is expected to disrupt normal splicing. In addition, one other clinical diagnostic laboratory classified this variant as likely pathogenic and another lab classified it as VUS, all without evidence for independent evaluation. This variant is absent in 114746 control chromosomes and it has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical and functional studies, the variant is classified as a VUS - possibly pathogenic, until additional information becomes available.

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