ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.509G>A (p.Cys170Tyr) (rs1057521111)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442726 SCV000521097 uncertain significance not provided 2016-08-02 criteria provided, single submitter clinical testing The C165Y variant in the MEN1 gene has previously been reported in at least one individual withmultiple endocrine neoplasia type 1 (MEN1); however no other clinical or family history informationwas provided (Ellard et al., 2005). The C165Y variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations.This variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. The C165Y substitution occurs at a position that isconserved across species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. This variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, which would further clarify its pathogenicity. Based on the currently available evidence, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. We consider it to be a variant of uncertain significance.
Invitae RCV000632126 SCV000753230 uncertain significance Multiple endocrine neoplasia, type 1 2017-09-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 165 of the MEN1 protein (p.Cys165Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual undergoing genetic testing for multiple endocrine neoplasia type 1 (MEN1) (PMID: 15670192). ClinVar contains an entry for this variant (Variation ID: 381624). 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.Cys165Arg) has been determined to be likely pathogenic (PMID: 17853334, 24756045, 12112656). This suggests that the cysteine 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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