ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4986+3G>C (rs80358023)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048721 SCV000076734 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast and/or ovarian cancer (PMID: 12491499, 23239986, 25971625, 18465347, 23772696, 25682074). This variant is also known as IVS16+3G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55341). 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 mRNA splicing (PMID: 23239986). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000162881 SCV000213368 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000112443 SCV000221136 pathogenic Breast-ovarian cancer, familial 1 2015-02-13 criteria provided, single submitter literature only
GeneDx RCV000236214 SCV000292524 likely pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+3G>C or IVS15+3G>C and consists of a G>C nucleotide substitution at the +3 position of intron 15 of the BRCA1 gene. This variant is also known as BRCA1 5105+3G>C or IVS16+3G>C using alternate nomenclature. In vitro RNA analysis demonstrated that this variant causes aberrant splicing, resulting in an out-of-frame intron inclusion predicted to result in protein truncation (Wappenschmidt 2012). This variant has been observed in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Adem 2003, Thomassen 2008, Muendlein 2015, Wong-Brown 2015, Dudley 2018). BRCA1 c.4986+3G>C was not observed in large population cohorts (Lek 2016). The guanine (G) nucleotide that is altered is not conserved. Based on currently available evidence, we consider BRCA1 c.4986+3G>C to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112443 SCV000326080 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048721 SCV000591552 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236214 SCV000605896 likely pathogenic not provided 2018-06-30 criteria provided, single submitter clinical testing
Color RCV000162881 SCV000688528 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
GeneKor MSA RCV000236214 SCV000693496 likely pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112443 SCV000145233 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 RCV000048721 SCV000587438 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research

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