ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.683T>C (p.Leu228Pro) (rs886039415)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255095 SCV000321880 pathogenic not provided 2016-02-05 criteria provided, single submitter clinical testing The L223P missense variant in the MEN1 gene has been reported previously in individuals with multiple endocrine neoplasia type 1 (Giraud et al., 1998; Crepin et al., 2003; Pieterman et al., 2012). The L223P variant was not observed in approximately 6,500 individuals of European or African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L223P variant is a semi-conservative amino acid substition, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Missense variants in nearby residues (W220S, W220L, G225R, S226P) have been reported in the Human Gene Mutation Database in association with MEN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is considered pathogenic.
Ambry Genetics RCV000491535 SCV000579636 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV001235431 SCV001408116 likely pathogenic Multiple endocrine neoplasia, type 1 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 223 of the MEN1 protein (p.Leu223Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with multiple endocrine neoplasia type 1 (PMID: 9683585, 12112656, 10849016, Invitae). This variant is also known in the literature as c.683T>C (p.Leu228Pro). ClinVar contains an entry for this variant (Variation ID: 265236). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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