Submissions for variant NM_001370259.2(MEN1):c.466G>A (p.Gly156Ser)

gnomAD frequency: 0.00001  dbSNP: rs1085307471

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702784	SCV000831653	likely pathogenic	Multiple endocrine neoplasia, type 1	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 156 of the MEN1 protein (p.Gly156Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 17623761). ClinVar contains an entry for this variant (Variation ID: 579486). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly156 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10090472, 29039523; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269816	SCV001450093	pathogenic	not provided	2014-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001269816	SCV002599631	likely pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with multiple endocrine neoplasia type 1 in published literature; however, this individual also harbored a second MEN1 variant (PMID: 17623761); This variant is associated with the following publications: (PMID: 35199646, 9989505, 17623761)
Ambry Genetics	RCV002332492	SCV002634389	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	clinical testing	The p.G156S variant (also known as c.466G>A), located in coding exon 2 of the MEN1 gene, results from a G to A substitution at nucleotide position 466. The glycine at codon 156 is replaced by serine, an amino acid with similar properties. This alteration has been identified in an individual with multiple endocrine neoplasia type 1 (MEN1); however, this individual also had another identified alteration in MEN1 (p.A160P), which has been identified in multiple probands with MEN1 phenotype (Tham E et al. J Clin Endocrinol Metab 2007 Sep;92(9):3389-95; Agarwal SK et al. Hum. Mol. Genet., 1997 Jul;6:1169-75; Wautot V et al. Hum. Mutat., 2002 Jul;20:35-47; Bassett JH et al. Am. J. Hum. Genet., 1998 Feb;62:232-44). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000702784	SCV004836546	uncertain significance	Multiple endocrine neoplasia, type 1	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 156 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 been reported in cis with MEN1 p.Ala160Pro in a family affected with multiple endocrine neoplasia type 1 (MEN1) (PMID: 17623761). The covariant, p.Ala160Pro, has been reported in multiple individuals affected with MEN1 (PMID: 9215689, 9463336, 12112656, 17623761) and has been shown in functional studies to impact MEN1 protein stability and protein-protein interactions (PMID: 9989505, 12509449, 21819486, 22090276) and it is also reported as disease-causing in ClinVar (variation ID: 579050). Other missense substitutions of glycine 156 with aspartic acid, arginine, cysteine and valine have been reported in individuals and families affected with MEN1 diagnosis and/or associated tumors (PMID: 10090472, 17623761, 17766710, 22026581, 28458907) and the former three substitutions have been reported as disease-causing in ClinVar (variation ID: 381625, 426144, 988303). An experimental study also has reported that p.Gly156Cys in the mouse protein results in protein instability (PMID: 21819486). 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.