ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197490 SCV000253714 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-30 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 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 been observed in an individual affected with breast cancer (PMID: 23239986). ClinVar contains an entry for this variant (Variation ID: 96936). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 23239986, 23451180, 30209399). For these reasons, this variant has been classified as Pathogenic.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Sharing Clinical Reports Project (SCRP) RCV000083057 SCV000115131 pathogenic Breast-ovarian cancer, familial 1 2011-01-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083057 SCV000145236 uncertain significance Breast-ovarian cancer, familial 1 2013-03-25 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000083057 SCV001243877 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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