ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000509904 SCV000608219 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing The c.301+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 4 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Alterations at this donor site are known to produce an in frame transcript impacting four amino acids in the BRCA1 RING domain (Ambry internal data). One functional study found that nucleotide substitutions at this donor site are non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). However a close match alteration with the same splice impact has been identified in trans with a pathogenic mutation in BRCA1 in an individual without features of Fanconi Anemia (Ambry internal data, personal communication). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000705646 SCV000834653 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-04 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.
Color Health, Inc RCV000509904 SCV000912053 likely benign Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing
GeneDx RCV001589310 SCV001825967 likely pathogenic not provided 2019-09-09 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30209399, 23239986)
Brotman Baty Institute,University of Washington RCV000258159 SCV001243802 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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