ClinVar Miner

Submissions for variant NM_001370259.2(MEN1):c.446-1G>A

dbSNP: rs1064793672
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487061 SCV000566743 pathogenic not provided 2015-05-22 criteria provided, single submitter clinical testing The c.446-1G>A splice site variant in the MEN1 gene destroys the canonical spliceacceptor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to anabnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormalprotein product if the message is used for protein translation. Although this variant hasnot been previously reported to our knowledge, we interpret it as pathogenic.
Ambry Genetics RCV001022519 SCV001184269 pathogenic Hereditary cancer-predisposing syndrome 2019-10-18 criteria provided, single submitter clinical testing The c.446-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the MEN1 gene. This alteration has been seen in multiple individuals with histories consistent with MEN1 syndrome (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV001851155 SCV002168514 pathogenic Multiple endocrine neoplasia, type 1 2021-09-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419140). Disruption of this splice site has been observed in individuals with multiple endocrine neoplasia type 1 (MEN1) syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 of the MEN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334).

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