ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1675C>T (p.Gln559Ter) (rs794728631)

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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 RCV000491870 SCV000579757 pathogenic Hereditary cancer-predisposing syndrome 2014-10-22 criteria provided, single submitter clinical testing
GeneDx RCV000182425 SCV000234770 pathogenic not provided 2015-06-29 criteria provided, single submitter clinical testing The Q554X nonsense mutation in the MEN1 gene has been reported previously in association with multiple endocrine neoplasia type 1 (Langer et al., 2001). This mutation is predicted to delete the last 57 amino acids of the protein, causing loss of normal protein function through protein truncation. The variant is found in MEN1 panel(s).
Invitae RCV000542312 SCV000628064 pathogenic Multiple endocrine neoplasia, type 1 2018-08-05 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 554 (p.Gln554*). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MEN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with multiple endocrine neoplasia type 1 (MEN 1) (PMID: 11578300, 17853334, 17158764). This variant is also known as c.1770C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 200988). This variant deletes the functionally conserved NLS2 domain 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). Another truncation (p.Lys559Glufs*38) that lies downstream of this variant has been reported in individuals affected with MEN1 (PMID: 10090472, Invitae). This suggests that deletion of this region of the MEN1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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