Submissions for variant NM_001370259.2(MEN1):c.281C>T (p.Thr94Ile)

dbSNP: rs1565651820

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701865	SCV000830687	uncertain significance	Multiple endocrine neoplasia, type 1	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 94 of the MEN1 protein (p.Thr94Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578759). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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.
Ambry Genetics	RCV002440514	SCV002752530	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-18	criteria provided, single submitter	clinical testing	The p.T94I variant (also known as c.281C>T), located in coding exon 1 of the MEN1 gene, results from a C to T substitution at nucleotide position 281. The threonine at codon 94 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV003222115	SCV003918397	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV000701865	SCV004194435	uncertain significance	Multiple endocrine neoplasia, type 1	2024-03-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000701865	SCV004827254	uncertain significance	Multiple endocrine neoplasia, type 1	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 94 of the MEN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MEN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000701865	SCV005684778	uncertain significance	Multiple endocrine neoplasia, type 1	2024-04-24	criteria provided, single submitter	clinical testing