ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.301+1G>T (rs587782173)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509943 SCV000607916 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000236488 SCV000294096 likely pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.301+1G>T or IVS5+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 5 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 420+1G>T. This 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 has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA1 c.301+1G>T to be a likely pathogenic variant.
Invitae RCV000802430 SCV000942262 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587782173, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 246510). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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