ClinVar Miner

Submissions for variant NM_001370259.2(MEN1):c.1279_1282dup (p.Pro428fs)

dbSNP: rs2136101131
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001812583 SCV002049708 pathogenic not provided 2020-10-28 criteria provided, single submitter clinical testing The MEN1 c.1279_1282dupAGTC; p. Pro428GlnfsTer22 variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with multiple endocrine neoplasia type 1 and are considered pathogenic (Romanet 2019, Wautot 2002). Based on available information, this variant is considered to be pathogenic. References: Romanet P et al. UMD-MEN1 Database: An Overview of the 370 MEN1 Variants Present in 1676 Patients From the French Population. J Clin Endocrinol Metab. 2019 Mar 1;104(3):753-764. Wautot V et al. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002 Jul;20(1):35-47.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869478 SCV002246053 pathogenic Multiple endocrine neoplasia, type 1 2023-07-29 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro428Glnfs*22) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the MEN1 protein. This variant has not been reported in the literature in individuals affected with MEN1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Thr580Argfs*8) have been determined to be pathogenic (PMID: 15331604, 16449969; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1331034).

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