ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Color RCV000581081 SCV000682951 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-22 criteria provided, single submitter clinical testing
Invitae RCV000705986 SCV000835013 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-05 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 conditions. ClinVar contains an entry for this variant (Variation ID: 245755). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 30209399). 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). For these reasons, this variant has been classified as Pathogenic.
Brotman Baty Institute,University of Washington RCV001075911 SCV001241564 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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