ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9648+1G>C (rs730881573)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160176 SCV000210514 pathogenic not provided 2014-02-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 IVS26+1G>C or c.9648+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 26 of the BRCA2 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 has not, to our knowledge, been published in the literature. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000817530 SCV000958096 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 26) of the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a 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 BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182265). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant is expected to affect a stretch of 36 conserved residues (amino acids Ala3270-Gly3305) in BRCA2 which are critical for RAD51-mediated DNA repair activity of the BRCA2 protein (PMID: 17515903, 24323938). While functional studies have not been performed to directly test the effect of this variant on BRCA2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239346 SCV000296628 pathogenic Breast-ovarian cancer, familial 2 2015-08-25 criteria provided, single submitter clinical testing

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