ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5194-2A>G (rs80358069)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131860 SCV000186915 pathogenic Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Other strong data supporting pathogenic classification
University of Washington Department of Laboratory Medicine, University of Washington RCV000031228 SCV000266034 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000256055 SCV000322128 likely pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5194-2A>G or IVS18-2A>G and consists of a A>G nucleotide substitution at the -2 position of intron 18 of the BRCA1 gene. Using alternate nomenclature, this variant has been previously published as BRCA1 5313-2A>G and IVS19-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in individuals with breast cancer and/or clinical features of Hereditary Breast/Ovarian Cancer syndrome (Esteban-Cardenosa 2004, Shirts 2016, Park 2017). Based on the currently available information, we consider BRCA1 c.5194-2A>G to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031228 SCV000326210 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000496913 SCV000591591 pathogenic Hereditary breast and ovarian cancer syndrome 2013-02-17 criteria provided, single submitter clinical testing
Color RCV000131860 SCV000683270 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496913 SCV000699220 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-29 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5194-2A>G 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. 5/5 computational tools predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.5194-2A>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Esteban-Cardenosa_2004, Shirts_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031228 SCV000053828 pathogenic Breast-ovarian cancer, familial 1 2011-04-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031228 SCV000145388 pathogenic Breast-ovarian cancer, familial 1 1999-06-21 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496913 SCV000587477 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000031228 SCV001237899 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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