ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.135-1G>A (rs80358158)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581081 SCV000682951 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
GeneDx RCV000235787 SCV000292844 pathogenic not provided 2016-10-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.135-1G>A or IVS3-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 3 of the BRCA1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to an abnormal protein product. Although this variant has not, to our knowledge, been published in the literature, another variant at this position, BRCA1 c.135-1G>T has been identified in individuals with breast and ovarian cancer and has been shown to result in skipping of exon 4 resulting in an in frame deletion (Shattuck-Eidens 1997, Risch 2001, Tesoriero 2005, Spurdle 2010). Although this deletion does not result in a frameshift, it does result in the loss of the RING finger functional domain (Paul 2014). Therefore, we consider BRCA1 c.135-1G>A to be pathogenic.
Invitae RCV000705986 SCV000835013 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 245755). 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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