Submissions for variant NM_001370259.2(MEN1):c.1A>G (p.Met1Val)

dbSNP: rs386134250

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030198	SCV000052865	likely pathogenic	Multiple endocrine neoplasia, type 1	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
GeneDx	RCV000480514	SCV000566017	likely pathogenic	not provided	2017-03-08	criteria provided, single submitter	clinical testing	The c.1 A>G variant in the MEN1 gene has previously been reported in at least one individual undergoing genetic testing for multiple endocrine neoplasia type 1 (Klein et al., 2005). This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. Based on currently available evidence, we consider c.1A>G to be a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded."
Ambry Genetics	RCV000491918	SCV000579617	pathogenic	Hereditary cancer-predisposing syndrome	2017-03-30	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the MEN1 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This pathogenic mutation has been reported in a family with familial isolated hyperparathyroidism. Note: In this paper the M1? (c.1A>G) pathogenic mutation was incorrectly referred to as L112V; however HGMD and the authors of this paper have verified that this represents the same mutation (Villablanca A et al. Eur. J. Endocrinol. 2002 Sep; 147(3):313-22). This pathogenic mutation has also been reported in another affected family however specific clinical information was not provided (Klein RD et al. Genet. Med. 2005 Feb; 7(2):131-8). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508430	SCV000604210	pathogenic	not specified	2016-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000030198	SCV000753247	pathogenic	Multiple endocrine neoplasia, type 1	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the MEN1 mRNA. The next in-frame methionine is located at codon 228. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia, type 1 (PMID: 28736585, 29036195; Invitae). ClinVar contains an entry for this variant (Variation ID: 36525). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000030198	SCV004175574	likely pathogenic	Multiple endocrine neoplasia, type 1	2021-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030198	SCV004836946	pathogenic	Multiple endocrine neoplasia, type 1	2023-10-02	criteria provided, single submitter	clinical testing	This variant disrupts the translation initiation codon of the MEN1 protein. The next in-frame methionine is at codon 228, which if used for translation initiation would truncate the N-terminal domain containing binding sites to lens epithelium-derived growth factor (LEDGF) and MLL1 (PMID: 22327296), therefore the loss of p.Met1 is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. The loss of the translation initiation codon has been reported in multiple individuals and families affected with multiple endocrine neoplasia, type 1 (PMID: 15714081, 26515642, 26767918, 28736585, 29036195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000030198	SCV001749849	not provided	Multiple endocrine neoplasia, type 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000480514	SCV001928119	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480514	SCV001953485	likely pathogenic	not provided		no assertion criteria provided	clinical testing