ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.461-3C>A (rs377461506)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000490866 SCV000579672 uncertain significance Hereditary cancer-predisposing syndrome 2014-01-09 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
Invitae RCV000531853 SCV000628083 uncertain significance Multiple endocrine neoplasia, type 1 2019-10-04 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the MEN1 gene. It does not directly change the encoded amino acid sequence of the MEN1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs377461506, ExAC 0.01%). This variant has not been reported in the literature in individuals with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 428028). 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 disrupts the c.446 3 nucleotide in the MEN1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10931102, 28693130). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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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