ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.355_357AAG[1] (p.Lys120del) (rs794728657)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491280 SCV000579630 pathogenic Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification
GeneDx RCV000182460 SCV000234805 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing The c.358_360delAAG variant in the MEN1 gene has been reported in many individuals clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) (for examples, see Agarwal et al., 1997; Mayr et al., 1998l Dackiw et al., 1999; Goroshi et al., 2016). Functional analyses demonstrate that this variant results in an unstable menin protein subject to rapid degradation and resulting in an 80% reduction in protein expression relative to wild-type (Shimazu et al., 2011). The c.358_360delAAG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.358_360delAAG variant is an in-frame deletion that results in the loss of a single Lysine residue, denoted p.Lys120del. The residue removed by this deletion is conserved across species. Based on currently available evidence, we consider c.358_360delAAG to be pathogenic.
Invitae RCV000018160 SCV000541188 pathogenic Multiple endocrine neoplasia, type 1 2019-01-07 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 2 of the MEN1 mRNA (c.358_360delAAG). This leads to the deletion of 1 amino acid residue in the MEN1 protein (p.Lys120del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs794728657, ExAC no frequency). This variant has been reported to segregate with hyperparathyroidism in a single family (PMID: 12807514). It has also been reported as one of the most common variants in individuals with multiple endocrine neoplasia type 1 (PMID: 9103196, 22470073, 17879353). This variant is also known as K119del in the literature. ClinVar contains an entry for this variant (Variation ID: 201019). Experimental studies have shown that this in-frame deletion destabilizes the MEN1 protein, likely as a result of protein misfolding, and leads to its degradation by the proteasome (PMID: 21819486, 15254225). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018160 SCV000038439 pathogenic Multiple endocrine neoplasia, type 1 1997-04-18 no assertion criteria provided literature only

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