ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.302-2delA (rs273899695)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130037 SCV000184863 pathogenic Hereditary cancer-predisposing syndrome 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Other strong data supporting pathogenic classification
Breast Cancer Information Core (BIC) (BRCA1) RCV000077534 SCV000144967 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077534 SCV000325536 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735535 SCV000863673 pathogenic Breast and/or ovarian cancer 2011-08-22 no assertion criteria provided clinical testing
GeneDx RCV000482044 SCV000566338 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.302-2delA or IVS5-2delA and consists of a deletion of the nucleotide at the -2 position of intron 5 of the BRCA1 gene. The normal sequence with the base that is deleted in brackets is ttac[dela]gATG, where the capital letters are exonic and lowercase are intronic. While the variant destroys a canonical splice acceptor site, it has been shown via RT-PCR to result in a frameshift, due to the activation of a cryptic splice acceptor site, leading to an abnormal protein product that is subject to nonsense-mediated mRNA decay (Southey 2003, Chen 2006). This variant, also published as 421-2delA or IVS6-2delA using alternate nomenclature, has been observed in several Hereditary Breast and Ovarian Cancer families (Shattuck-Eidens 1997, Gayther 1999, Southey 2003, Tesoriero 2005, Chen 2006). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000048047 SCV000076060 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5. It is expected to disrupt mRNA splicing and likely results in an absent or truncated protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple patients and families affected with breast and ovarian cancer (PMID: 9333265, 10486320, 12815598, 16619214, 20104584). It is also known as 421-2delA and IVS6-2delA in the literature. ClinVar contains an entry for this variant (Variation ID: 54753). Experimental studies have shown that this variant disrupts the natural acceptor splice site in intron 5, leading to the activation of a cryptic splice site located 10 nucleotides into exon 6 (PMID: 12815598, 16619214). Use of this new site is expected to result in a premature termination codon in the BRCA1 mRNA and nonsense-mediated decay. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048047 SCV000967734 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-16 criteria provided, single submitter clinical testing The c.302-2delA variant in BRCA1 has been reported in at least 16 individuals wi th breast and/or ovarian cancer (Shattuck-Eidens 1997, Gayther 1999, Southey 200 3, Chen 2006, Borg 2010, BIC database [https://research.nhgri.nih.gov/bic/]) and segregated with disease in at least 9 affected relatives from 1 family (Southey 2003). This variant has also been reported by other clinical laboratories in C linVar (Variation ID# 54753) and was absent from large population databases. Th e c.302-2delA variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. In vitro studies as well as sequencing of cDNA from individ uals with this variant showed that it leads to activation of a cryptic splice si te, leading to 10 bp frameshift at the beginning of the next exon and resulting in the addition of 14 new amino acid residues and a premature stop codon (Chen 2 006). In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer (HBOC) in an autosomal dominant manner bas ed upon presence in multiple affected individuals, segregation studies, absence from the general population, functional evidence, and predicted impact on the pr otein. ACMG/AMP Criteria applied (Richards 2015): PVS1, PS4, PP1_Strong.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482044 SCV000600313 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048047 SCV000587044 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077534 SCV000109335 pathogenic Breast-ovarian cancer, familial 1 2013-03-14 no assertion criteria provided clinical testing

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