ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1A>T (p.Met1Leu) (rs386134250)

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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 RCV000491567 SCV000579679 pathogenic Hereditary cancer-predisposing syndrome 2015-11-27 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Invitae RCV000536890 SCV000628072 pathogenic Multiple endocrine neoplasia, type 1 2019-02-20 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 (ExAC no frequency). Disruption of the initiator methionine has been observed in several individuals affected with multiple endocrine neoplasia type 1 (PMID: 28736585, 29036195, Invitae). ClinVar contains an entry for this variant (Variation ID: 428034). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000536890 SCV001160194 pathogenic Multiple endocrine neoplasia, type 1 2018-12-31 criteria provided, single submitter clinical testing The MEN1 c.1A>T; p.Met1? variant is reported in the literature in at least one individual affected with multiple endocrine neoplasia, type 1 (Concolino 2016). This variant is reported in ClinVar (Variation ID: 428034), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant affects the initiation codon and is predicted to affect the protein translation start site. Additionally, other variants affecting the initiation codon (c.1A>G, p.Met1?; c.2T>A, p.Met1?) have been reported in individuals with multiple endocrine neoplasia, type 1 and are considered pathogenic (Kaiwar 2017, Klein 2005, Pardi 2017, Remde 2015). Based on available information, the c.1A>T; p.Met1? variant is considered to be pathogenic. References: Concolino P et al. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41. Kaiwar C et al. Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1. Hered Cancer Clin Pract. 2017 Jul 21;15:10. 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. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Remde H et al. A patient with novel mutations causing MEN1 and hereditary multiple osteochondroma. Endocrinol Diabetes Metab Case Rep. 2015;2015. pii: 14-0120.

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