ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1397_1404dup (p.Ala469fs) (rs1114167531)

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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 RCV000491754 SCV000579737 pathogenic Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000632114 SCV000753218 pathogenic Multiple endocrine neoplasia, type 1 2017-08-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MEN1 gene (p.Ala464Argfs*98). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acids of the MEN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with multiple endocrine neoplasia type 1 (PMID: 12050235). ClinVar contains an entry for this variant (Variation ID: 428075). This frameshift disrupts 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). In addition, a different frameshift variant (p.Arg516Glyfs*43) with a premature termination codon downstream of this frameshift has been reported to be a common cause of multiple endocrine neoplasia type 1 (PMID: 17879353) For these reasons, this variant has been classified as Pathogenic.

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