ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.541G>T (p.Ala181Ser) (rs376872829)

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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 RCV000573513 SCV000673639 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneKor MSA RCV000573513 SCV000822017 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000632090 SCV000753194 uncertain significance Multiple endocrine neoplasia, type 1 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 176 of the MEN1 protein (p.Ala176Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs376872829, ExAC 0.002%). This variant has not been reported in the literature in individuals with MEN1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Ala176Pro) has been determined to be pathogenic (PMID: 22090276, 9215689). This suggests that the alanine residue is critical for MEN1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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