ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5193+1G>T (rs80358004)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160001 SCV000210206 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5193+1G>T or IVS18+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 18 of the BRCA1 gene. The variant destroys a canonical splice donor 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, also defined as 5312+1G>T or IVS19+1G>T using alternate nomenclature or exon numbering, has been reported in at least two individuals with breast cancer and one with ovarian cancer (Spurdle 2008, Seifert 2016). In a functional study, this variant was classified as non-functional based on a saturation genome editing (SGE) assay measuring growth in a BRCA1 null cell line (Findlay 2018). Based on current evidence, we consider this variant to be pathogenic.
Invitae RCV000496615 SCV000940677 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects a donor 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 observed in individuals affected with ovarian cancer and peritoneal cancer (PMID: 27083775, 26681312). ClinVar contains an entry for this variant (Variation ID: 91642). 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). 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.
Sharing Clinical Reports Project (SCRP) RCV000077159 SCV000108956 pathogenic Breast-ovarian cancer, familial 1 2010-05-18 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496615 SCV000587476 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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