Submissions for variant NM_001370259.2(MEN1):c.1429G>T (p.Glu477Ter)

dbSNP: rs863224526

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198067	SCV000253966	pathogenic	Multiple endocrine neoplasia, type 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu477*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 134 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia 1 (MEN1) (PMID: 12049533, 15714081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216133). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation (PMID: 15331604, 16449969). While functional studies have not been performed to directly test the effect of this variant on MEN1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000254822	SCV000321888	pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Identified in patients with multiple endocrine neoplasia type 1 referred for genetic testing at this laboratory and in published literature (Cote 1998, Dackiw 1999, Kouvaraki 2002, Klein 2005); This variant is associated with the following publications: (PMID: 15714081, 17879353, 12049533, 10660339, 10598193, 15281352)
Ambry Genetics	RCV000490934	SCV000579669	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The p.E477* pathogenic mutation (also known as c.1429G>T), located in coding exon 9 of the MEN1 gene, results from a G to T substitution at nucleotide position 1429. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 134 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been detected in seven affected members of one family (Kouvaraki MA et al. Arch Surg. 2002 Jun;137(6):641-7). In addition to the clinical data presented in the literature, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000254822	SCV001158284	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	The MEN1 c.1429G>T; p.Glu477Ter variant (rs863224526) is reported in the medical literature in individuals and families with a clinical diagnosis of multiple endocrine neoplasia type 1 (Dackiw 1999, Klein 2005, Kouvaraki 2002). The variant is described as pathogenic in the ClinVar database (Variation ID: 216133) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Considering available information, this variant is classified as pathogenic. References: Dackiw AP et al. Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Surgery. 1999 Dec;126(6):1097-103. PMID: 10598193. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID: 15714081. Kouvaraki MA et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg. 2002 Jun;137(6):641-7. PMID: 12049533.
Revvity Omics, Revvity	RCV000198067	SCV002024336	pathogenic	Multiple endocrine neoplasia, type 1	2019-08-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000198067	SCV002547634	pathogenic	Multiple endocrine neoplasia, type 1	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: MEN1 c.1429G>T (p.Glu477X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 225462 control chromosomes. c.1429G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (eg. Cote_1998, Dackiw_1999, Klein_2005, Kouvaraki_2002, etc). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254822	SCV002774387	pathogenic	not provided	2021-07-28	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MEN1 protein synthesis. In addition, it has been reported in symptomatic individuals with multiple endocrine neoplasia 1 in the published literature (PMIDs: 12049533 (2002) and 15714081 (2005)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000198067	SCV004019132	pathogenic	Multiple endocrine neoplasia, type 1	2023-02-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.