ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4986+5G>A (rs397509211)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Breast Cancer Information Core (BIC) (BRCA1) RCV000083057 SCV000145236 uncertain significance Breast-ovarian cancer, familial 1 2013-03-25 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083057 SCV000326083 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000197490 SCV000918764 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-21 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4986+5G>A variant (alternatively known as IVS16+5G>A and 5105+5G>A) involves the alteration of a conserved intronic nucleotide and is predicted to impact splicing by 4/5 splice prediction tools. Mutation taster also predicts a damaging outcome for this variant. This variant is absent in 244498 control chromosomes (gnomAD). This variant has been reported in breast and pancreatic cancer patients in the literature (Wappenschmidt_2012, Mandelker_2017) and functional studies show that it leads to the retention of 65 nucleotides of the 5' end of intron 15 which leads to premature truncation of the BRCA1 protein (p.Met1663Valfs*14) (Wappenschmidt_2012, Colombo_2013). Other similar variants (c.4986+3G>C, c.4986+4A>G, c.4986+5G>T and c.4986+6T>C) were found to cause the incorporation of the 65 intronic nucleotides [Wappenschmidt_2012, Vreeswijk_2009 (PMID: 18693280)]. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000197490 SCV000253714 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-05-10 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 mRNA. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant has been reported in affected patients in the Breast Cancer Information Core database (PMID: 10923033) and is absent from population databases. Clinvar contains an entry for this variant (RCV000083057). In summary, this is a rare sequence change which has been shown to cause the generation of a truncated BRCA1 protein. For these reasons, this variant has been classified as Likely Pathogenic. In an experimental study that evaluated the effect of this sequence change on the production of BRCA1 mRNA, it was reported to cause intronic retention of 65bps at the 5' end of exon 16, which eventually resulted in the generation of a truncated BRCA1 mRNA (PMID: 23451180). Furthermore, another sequence change affecting the same nucleotide has also been shown to result in intronic retention and the generation of a truncated protein product (PMID:18693280). Truncating variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Sharing Clinical Reports Project (SCRP) RCV000083057 SCV000115131 pathogenic Breast-ovarian cancer, familial 1 2011-01-24 no assertion criteria provided clinical testing

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