ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074G>A (p.Asp1692Asn) (rs80187739)

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Total submissions: 9
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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 The c.5074G>A variant (also known as p.D1692N), located in coding exon 15 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5074. The amino acid change results in aspartic acid to asparagine at codon 1692, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site, and was demonstrated via mini gene splicing assays to result in the skipping of exon 17 and to use a cryptic splice donor site to generate a 418bp product which contains 153 bp of intron 17 at the mRNA level (Ahlborn LB, et al. Breast Cancer Res.Treat. 2015;150(2):289-98). One study used linkage analysis to suggest that this variant may be an Icelandic founder mutation (Bergthorsson JT, et al. Hum. Mutat. 1998 ; Suppl 1():S195-7.), while another predicted it to be pathogenic by using sequence alignment technologies and grantham chemical difference scores (Abkevich V, et al. J. Med. Genet. 2004;41(7):492-507). This variant is located in the functionally important BRCT domain, and has been reported in several studies to have little or no destabilizing activity; however, as authors pointed out, these studies performed on artificial DNA (cell and mammalian based cDNA) are not accurate representations of processes occurring at the mRNA level (Rowling PJ, et al. J. Biol. Chem. 2010;285(26):20080-7; Lee MS, et al. Cancer Res. 2010;70(12):4880-90; Vallon-Christersson J, et al. Hum. Mol. Genet. 2001;10(4):353-60). Of note, this alteration is also designated as 5193G>A in published literature. This nucleotide and amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 Health, Inc RCV000217586 SCV000904696 pathogenic Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Invitae RCV000496924 SCV001585898 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1692 of the BRCA1 protein (p.Asp1692Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 16 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 9452084, 10196379). It has been reported to segregate with disease in the affected families, and has also been described as a rare founder mutation in the Icelandic population (PMID: 9452084, 8460636, 15571962). This variant is also known as 5193G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37632). 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 BRCA1 mRNA splicing and protein function (PMID: 30209399, 25748678, 25724305). A different variant affecting this nucleotide (c.5074G>C) has been determined to be pathogenic (PMID: 21769658, 22762150, 22505045, 23239986, 25724305, 30209399). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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
Brotman Baty Institute,University of Washington RCV000031213 SCV001244020 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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