ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1444G>T (p.Glu482Ter) (rs863224526)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198067 SCV000253966 pathogenic Multiple endocrine neoplasia, type 1 2019-07-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the MEN1 mRNA at codon 477 (p.Glu477*). It is not anticipated to result in an absent protein by nonsense mediated decay but is expected to create a truncated MEN1 protein missing the C-terminal 134 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in families affected with multiple endocrine neoplasia 1 (MEN1) (PMID: 12049533, 15714081). ClinVar contains an entry for this variant (Variation ID: 216133). This variant, located in the last exon (10), is predicted to result in a truncated MEN1 protein missing an important nuclear localization signal (NLS). Loss of the NLS domain has been shown to disrupt the functional activities of the MEN1 protein (PMID: 16449969). and several other truncating variants in this exon have been reported to be pathogenic (PMID: 15714081). Therefore, the p.Glu477* truncation is expected to be deleterious. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000254822 SCV000321888 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.1429G>T at the cDNA level and p.Glu477Ter (E477X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with features of multiple endocrine neoplasia type 1 (Cote 1998, Dackiw 1999, Kouvaraki 2002, Klein 2005) and is considered pathogenic.
Ambry Genetics RCV000490934 SCV000579669 pathogenic Hereditary cancer-predisposing syndrome 2014-07-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000198067 SCV001158284 pathogenic Multiple endocrine neoplasia, type 1 2019-03-13 criteria provided, single submitter clinical testing The MEN1 c.1429G>T; p.Glu477Ter variant (rs863224526) is reported in the medical literature in individuals and families with a clinical diagnosis of multiple endocrine neoplasia type 1 (Dackiw 1999, Klein 2005, Kouvaraki 2002). The variant is described as pathogenic in the ClinVar database (Variation ID: 216133) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Considering available information, this variant is classified as pathogenic. References: Dackiw AP et al. Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Surgery. 1999 Dec;126(6):1097-103. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. Kouvaraki MA et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg. 2002 Jun;137(6):641-7.

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