ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1102_1104del (p.Glu368del) (rs869025185)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255250 SCV000321883 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MEN1 is denoted c.1087_1089delGAG at the cDNA level and p.Glu363del (E363del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAG[delGAG]TTCT. This variant was observed in several individuals with a personal and/or family history of Multiple Endocrine Neoplasia type 1, and was found to segregate with disease in at least one large kindred with Familial Isolated Hyperparathyroidism (Agarwal 1997, Miedlich 2001, Turner 2002, Long 2007). On functional interrogation, Shimazu et al. (2011) found this variant to decrease menin protein expression and stability. MEN1 Glu363del was not observed in large population cohorts (Lek 2016). This deletion of a single Glutamic Acid amino acid is located in a region that interacts with FANCD2 (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on current evidence, we consider this variant to be pathogenic.
Invitae RCV000018165 SCV000541178 pathogenic Multiple endocrine neoplasia, type 1 2019-04-30 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 8 of the MEN1 mRNA (c.1087_1089delGAG). This leads to the deletion of 1 amino acid residue in the MEN1 protein (p.Glu363del) but otherwise preserves the integrity of the reading frame. 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, and was shown to segregate with hyperparathyroidism in one family (PMID: 9215689, 12050235, 22026581, 11454510). ClinVar contains an entry for this variant (Variation ID: 16685). An experimental study has shown that this variant destabilizes the MEN1 protein, leading to its degradation by the proteasome (PMID: 21819486). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491660 SCV000579625 pathogenic Hereditary cancer-predisposing syndrome 2017-12-28 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
OMIM RCV000018165 SCV000038444 pathogenic Multiple endocrine neoplasia, type 1 1997-04-18 no assertion criteria provided literature only

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