ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.547+2T>A (rs80358047)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031255 SCV000282246 pathogenic Breast-ovarian cancer, familial 1 2016-04-03 reviewed by expert panel curation Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.442_547del transcript (encoding predicted non-functional protein).
Invitae RCV000034759 SCV000077022 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 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 observed in several individuals affected with breast and/or ovarian cancer (PMID: 9333265, 23940062, 25556971). This variant is also known as IVS8+2T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37674). Experimental studies have shown that this variant causes skipping of exon 7, also called exon 8 in the literature, and is expected to lead to a premature stop codon (p.Gln148Aspfs*51) (PMID: 23451180, 22505045, 24667779). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031255 SCV000296429 pathogenic Breast-ovarian cancer, familial 1 2016-03-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031255 SCV000326327 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000481282 SCV000568433 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.547+2T>A or IVS7+2T>A and consists of a T>A nucleotide substitution at the +2 position of intron 7 of the BRCA1 gene. Using alternate nomenclature, this variant has previously been published as BRCA1 IVS8+2T>A. This variant destroys a canonical splice donor site and causes abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. RNA studies including in vitro RT-PCR and minigene assays have demonstrated skipping of exon 8, also known as exon 7 using alternate exon numbering, due to this variant (Houdayer 2012, Colombo 2013, Steffensen 2014). BRCA1 c.547+2T>A was observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens 1997, Turner 1999, Smith 2000, Grushko 2004, Johnston 2012, Colombo 2013). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000563139 SCV000665799 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000031255 SCV000785772 pathogenic Breast-ovarian cancer, familial 1 2017-11-27 criteria provided, single submitter clinical testing
Color RCV000563139 SCV000905208 pathogenic Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034759 SCV000043187 pathogenic Hereditary breast and ovarian cancer syndrome 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031255 SCV000053859 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031255 SCV000145615 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 RCV000034759 SCV000587064 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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