ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5074G>A (p.Asp1692Asn) (rs80187739)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217586 SCV000273244 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Last nucleotide of exon;Functionally-validated splicing mutation
GeneDx RCV000255870 SCV000322096 likely pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5074G>A at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 5193G>A. Although the nucleotide substitution results in the change of an Aspartic Acid to an Asparagine at codon 1692, and is called Asp1692Asn (D1692N) in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than the resulting missense variant. This variant was not observed in large population cohorts (Lek 2016). BRCA1 c.5074G>A has been reported in breast and ovarian cancer cases, and has been described as an Icelandic founder pathogenic variant (Bergthorsson 1998, Janezic 1999, Rafnar 2004). Located in the last nucleotide of exon 16 (published as exon 17 using alternate exon numbering) in silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. An in vitro study by Ahlborn et al. (2015) demonstrated that this exonic splicing variant leads to multiple aberrant transcripts, with one alternate transcript causing skipping of exon 17 and another causing activation of a cryptic splice donor site, leading to an in-frame retention of 153 nucleotides within the spliced transcript. Although Wappenschmidt et al. (2012) identified exon 17 skipping in control samples, indicating it may be a naturally occurring BRCA1 isoform, the level of this alternate transcript in controls was low. While other functional studies have demonstrated normal protein folding, transcriptional, and homology-directed repair activities (Vallon-Christersson 2001, Mirkovic 2004, Lee 2010, Gaboriau 2015), these assays interrogated the impact of the resulting missense change as opposed to a splicing defect, and these findings do not take away from the significance of the splicing data. In summary, significant in vitro evidence suggests pathogenicity, although given the alternate splicing mechanism of the variant, the in vivo effect is less clear. Based on the currently available evidence, we consider BRCA1 c.5074G>A to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031213 SCV000326135 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000217586 SCV000904696 pathogenic Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031213 SCV000053813 likely pathogenic Breast-ovarian cancer, familial 1 2006-07-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031213 SCV000145293 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496924 SCV000587454 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research

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