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 likely pathogenic Multiple endocrine neoplasia, type 1 2017-11-19 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MEN1 mRNA. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (PMID: 10612827) Two other different substitutions at this codon (c.1A>G and c.2T>A) have been reported in individuals affected with multiple endocrine neoplasia type I (MEN1) (PMID: 15714081, 26515642, Invitae database) and determined to be pathogenic. This suggests that the initiator methionine residue is critical for MEN1 protein function and that other missense substitutions at this position may also be pathogenic. 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.
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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