ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1393C>T (p.Arg465Ter) (rs104894267)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129526 SCV000184302 pathogenic Hereditary cancer-predisposing syndrome 2017-05-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000182421 SCV000234766 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.1378C>T at the cDNA level and p.Arg460Ter (R460X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. Even though this truncation occurs near the end of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 151 amino acids are no longer translated. MEN1 Arg460Ter has been reported in many individuals with multiple endocrine neoplasia type 1 and tracked with disease in four large Newfoundland kindreds (Olufemi 1998, Verges 2002, Matsuzaki 2004, Belar 2012, Christakis 2016). In vitro assays demonstrated that this variant results in a 90% reduction of protein expression relative to the wild-type (Shimazu 2011). This variant is considered pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000182421 SCV000700503 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000182421 SCV000885689 pathogenic not provided 2017-08-25 criteria provided, single submitter clinical testing
Invitae RCV000018172 SCV000953567 pathogenic Multiple endocrine neoplasia, type 1 2019-12-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MEN1 gene (p.Arg460*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acids of the MEN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals and families affected with multiple endocrine neoplasia type 1 (PMID: 17879353, 9215689, 18753103, 14678300, 19461164). ClinVar contains an entry for this variant (Variation ID: 16692). This variant has been reported to reduce MEN1 protein expression (PMID: 21819486). This sequence change disrupts the functionally conserved nuclear localization signal of the MEN1 protein (amino acid 588-608). 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). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018172 SCV000038451 pathogenic Multiple endocrine neoplasia, type 1 1998-01-01 no assertion criteria provided literature only

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