ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.541G>C (p.Ala181Pro) (rs376872829)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505771 SCV000234751 likely pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing The A176P missense variant in the MEN1 gene has previously been published in association with multiple endocrine neoplasia type 1 (Agarwal et al., 1997; Marx et al., 1998). Functional studies demonstrate that A176P results in reduced protein expression compared to wild-type, and that the resulting protein product is unstable (Canaff et al., 2012). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A176P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, A176P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Ambry Genetics RCV000491572 SCV000579682 likely pathogenic Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Structural Evidence
Invitae RCV000551917 SCV000628085 likely pathogenic Multiple endocrine neoplasia, type 1 2017-08-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 176 of the MEN1 protein (p.Ala176Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with multiple endocrine neoplasia type 1 (PMID: 9215689). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 200975). Experimental studies have shown that this missense change disrupts homologous recombination-directed DNA repair and reduces the inhibition of JunD-mediated transcriptional activity  (PMID: 22090276, 12509449, 9989505, 23648481, 11221882). 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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