Submissions for variant NM_000244.3(MEN1):c.482G>A (p.Gly161Asp) (rs794728648)

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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	RCV000491482	SCV000579642	pathogenic	Hereditary cancer-predisposing syndrome	2012-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000425558	SCV000521098	likely pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing	The mosaic G156D variant in the MEN1 gene has previously been reported in association with multiple endocrine neoplasia type 1 (Mutch et al., 1999; de Laat et al., 2014). This variant was not observed in approximately 6,500 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 G156D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. Missense variants at the same residue (G156S, G156C, G156R,G156V) have been reported in the Human Gene Mutation Database in association with multiple endocrine neoplasia type 1 (Tham et al., 2007; Vierimaa et al., 2007; Belar et al., 2012; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, G156D is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV000466874	SCV000541184	uncertain significance	Multiple endocrine neoplasia, type 1	2016-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 156 of the MEN1 protein (p.Gly156Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 families affected with MEN1-related disorders (PMID: 10090472, 11034102). Several missense substitution at this codon (p.Gly156Ser, p.Gly156Arg, p.Gly156Cys, and Gly156Val) have been reported in individuals affected with MEN1-related disorders (PMID: 17623761, 17766710, 22026581, 21819486), although their pathogenicity is uncertain. This suggests that the glycine residue might be important for MEN1 protein function. 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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