ClinVar Miner

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

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Total submissions: 13
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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 The c.5194-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 18 in the BRCA1 gene. This mutation was detected in 2/82 Norwegian patients with breast and/or ovarian cancer who also had a family history that was concerning for hereditary breast and ovarian cancer (HBOC) syndrome (Møller P et al. Eur. J. Cancer. 2001 May;37:1027-32). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
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
Color Health, Inc RCV000131860 SCV000683270 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV000496913 SCV001579182 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 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 individuals affected with breast cancer (PMID: 14684619, 26845104), and in Leiden Open-source Variation Database (PMID: 21520333) and Breast Cancer Information Core database (PMID: 10923033). This variant is also known as 5313-2A>G or IVS19-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37647). A different variant affecting this nucleotide (c.5194-2A>C) has been determined to be pathogenic (PMID: 22333603). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Research and Development, ARUP Laboratories RCV001659889 SCV001877466 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2021-05-01 criteria provided, single submitter curation
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353945 SCV000591591 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The c.5194-2A>G variant has been previously reported as disease-causing in the BIC and UMD databases and in the literature (Esteban-Cardeñosa 2003), however, no normal population controls were included in this study. This variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant -1 and -2 positions of the splice consensus sequence located in the 3' splice region of BRCA1. It is listed in the dbSNP database (ID#: rs80358069) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. In summary, based on the above information this variant is classified as pathogenic.
Brotman Baty Institute,University of Washington RCV000031228 SCV001237899 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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