ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.843C>A (p.Tyr281Ter) (rs1060503789)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484977 SCV000565128 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.828C>A at the cDNA level and p.Tyr276Ter (Y276X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with multiple endocrine neoplasia type 1 (Kouvaraki 2002, Schaaf 2007, Ye 2017) and is considered pathogenic.
Ambry Genetics RCV000491793 SCV000579671 pathogenic Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000823755 SCV000964625 pathogenic Multiple endocrine neoplasia, type 1 2019-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr276*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families affected with multiple endocrine neoplasia type 1 (PMID: 12049533, 17853334). This variant is also known as c.938C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 418292). Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000484977 SCV001144497 pathogenic not provided 2019-07-18 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000823755 SCV001156566 pathogenic Multiple endocrine neoplasia, type 1 2018-09-20 criteria provided, single submitter clinical testing The MEN1 c.828C>A; p.Tyr276Ter variant, is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 1 (Kouvaraki 2002, Schaaf 2007, Ye 2017). This variant is reported as pathogenic by in ClinVar (Variation ID: 418292) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other downstream nonsense variants in MEN1 have been identified in individuals affected with multiple endocrine neoplasia type 1 and are considered pathogenic (Agarwal 1997, Bassett 1998). Based on available information, the p.Tyr276Ter variant is considered to be pathogenic. References: Agarwal SK et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 1997 Jul;6(7):1169-75. Bassett JH et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 1998 Feb;62(2):232-44. Kouvaraki MA et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg. 2002 Jun;137(6):641-7. Schaaf L et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp Clin Endocrinol Diabetes. 2007 Sep;115(8):509-17. Ye L et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf). 2017 Dec;87(6):706-716.

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