ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.227C>A (p.Thr76Asn) (rs886039752)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255896 SCV000322706 uncertain significance not provided 2016-09-13 criteria provided, single submitter clinical testing The T76N variant in the MEN1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,400 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 T76N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on currently available evidence, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001246047 SCV001419377 uncertain significance Multiple endocrine neoplasia, type 1 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 76 of the MEN1 protein (p.Thr76Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 265710). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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