ClinVar Miner

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

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Total submissions: 3
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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 The c.1382_1389dupAGGCCGAG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of AGGCCGAG at nucleotide position 1382, causing a translational frameshift with a predicted alternate stop codon (p.A464Rfs*98). This same 8 base pair duplication, referred to as "fs 96 aa X", was detected in 1 of 34 unrelated MEN1 probands (Turner JJ, J. Clin. Endocrinol. Metab. 2002 Jun; 87(6):2688-93). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287863 SCV001474604 likely pathogenic none provided 2019-10-15 criteria provided, single submitter clinical testing The MEN1 c.1382_1389dup; p.Ala464fs variant (rs1114167531) is reported in the literature in individuals with multiple endocrine neoplasia type 1 (Pardi 2017, Turner 2002), and is classified as pathogenic in ClinVar (Variation ID: 428075). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a frameshift in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to disrupt the last 147 amino acids of the MEN1 protein. This frameshift disrupts a well-conserved nuclear localization signal of the MEN1 protein and functional assays demonstrate this regions importance for regulating gene expression and cell proliferation (La 2004 and 2006). Based on available information, this variant is considered to be pathogenic. REFERENCES La P et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem. 2004 Nov 19;279(47):49045-54. La P et al. Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. Oncogene. 2006 Jun 15;25(25):3537-46. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Turner JJ et al. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2002 Jun;87(6):2688-93.

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