ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5153-2delA (rs273901746)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129629 SCV000184422 pathogenic Hereditary cancer-predisposing syndrome 2016-03-09 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,Functionally-validated splicing mutation
Breast Cancer Information Core (BIC) (BRCA1) RCV000077603 SCV000145355 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129629 SCV000683263 pathogenic Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077603 SCV000326183 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077603 SCV000488462 pathogenic Breast-ovarian cancer, familial 1 2016-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000479617 SCV000566340 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5153-2delA or IVS17-2delA and consists of a deletion of one nucleotide at the -2 position of intron 17 of the BRCA1 gene. The variant destroys a canonical splice acceptor site and has been shown through RT-PCR to cause abnormal gene splicing (Wappenschmidt 2012). It is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, as was shown by Perrin-Vidoz et al. (2002), or to an abnormal protein product. This variant, also published as BRCA1 5272-2delA or IVS18-2delA using alternate nomenclature, has been observed in association with Hereditary Breast and Ovarian Cancer syndrome (Kiechle 2000, Sinilnikova 2006, Pern 2012, Kang 2015). Based on the current evidence, we consider this variant to be pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785423 SCV000923995 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000048829 SCV000916812 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5153-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site, which is supported by a functional study (Wappenschmidt_2012). The variant was absent in 250880 control chromosomes (gnomAD). c.5153-2delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Grushko_2004, Kiechle_2002, Pern_2012, Perrin-Vidoz_2002, Wappenschmidt_2012). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000048829 SCV000076842 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with a personal and/or family history of breast and ovarian cancer (PMID: 11102986, 12393792, 16528604, 23110154, 23239986, 25863477). This variant is also known as 5272-2delA and IVS18-2delA in the literature. ClinVar contains an entry for this variant (Variation ID: 55431). Analysis of patient lymphocyte mRNA has shown that this variant causes aberrant splicing and skipping of exon 18 (referred to as exon 19), which would result in a frameshift and truncated protein (PMID: 23239986, 12393792). 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 RCV000048829 SCV000605761 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The c.5153-2delA variant in BRCA1 has been identified 9 individuals with BCRA1-a ssociated cancers and segregated with disease in 4 affected relatives from 1 fam ily (Kiechle 2000; Breast Cancer Information Core (BIC) database). It was also a bsent from large population studies. This variant is a deletion of one nucleotid e in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. In sum mary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer (HBOC) in an autosomal dominant manner.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048829 SCV000587471 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077603 SCV000109406 pathogenic Breast-ovarian cancer, familial 1 2010-08-10 no assertion criteria provided clinical testing

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