ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1421_1428dup (p.Gly477fs) (rs1114167536)

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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 RCV000491271 SCV000579744 pathogenic Hereditary cancer-predisposing syndrome 2018-06-04 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000532169 SCV000628046 pathogenic Multiple endocrine neoplasia, type 1 2018-01-19 criteria provided, single submitter clinical testing This sequence change inserts 8 nucleotide in exon 10 of the MEN1 mRNA (c.1406_1413dupAGCCGTGG), causing a frameshift at codon 472. This creates a premature translational stop signal in the last exon of the MEN1 mRNA (p.Gly472Serfs*90). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 138 amino acids of the MEN1 protein. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in MEN1 are known to be pathogenic. This particular variant has been reported in the literature in individuals with a personal or family history of multiple endocrine neoplasia type 1 (PMID: 19491073, 15714081). In the literature this variant is reported to cause a frame shift starting at codon 469. This variant truncates the functionally conserved nuclear localization signal of the MEN1 protein. Experimental studies have shown that disruption of this region abrogates the ability of MEN1 to bind DNA, regulate target gene expression, and inhibit cell proliferation (PMID: 15331604, 16449969). For these reasons, this variant has been classified as Pathogenic.

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