ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.301+1G>C (rs587782173)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509904 SCV000608219 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000509904 SCV000912053 likely benign Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258159 SCV000325525 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000705646 SCV000834653 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587782173, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 267517). An experimental study has shown that a different variant (c.301+6T>C) affecting a nucleotide within the consensus splice site of the intron results in an aberrant transcript encoding an in-frame deletion of 3 amino acids at the exon 5-6 junction (referred to as the exon 6-7 junction) (PMID: 21769658). While the effect of this variant (c.301+1G>C) has not been assessed experimentally, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant disrupts the consensus splice site and creates a cryptic donor splice site 9 nucleotides upstream, leading to the in-frame loss of 3 amino acids. This is similarly predicted and experimentally demonstrated for c.301+6T>C. These data suggest that an upstream, cryptic donor site can potentially rescue disruption of the canonical donor site, thereby preserving the integrity of the reading frame. 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.

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