ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7435+3A>G (rs876661289)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222932 SCV000279998 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7435+3A>G or IVS14+3A>G and consists of a A>G nucleotide substitution at the +3 position of intron 14 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7663+3A>G. BRCA2 c.7435+3A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The adenine (A) nucleotide that is altered is conserved across species. In silico splicing models are uninformative. Based on currently available information, it is unclear whether BRCA2 c.7435+3A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000467006 SCV000549821 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-08 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. 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: 234911). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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