ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1561del (p.Arg521fs) (rs767319284)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182439 SCV000234784 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing The c.1546delC pathogenic variant in the MEN1 gene has been reported previously in association with multiple endocrine neoplasia type 1 (MEN1) using alternate nomenclature (Agarwal et al., 1997; Giraud et al., 1998). The normal sequence with the base that is deleted in braces is: ACCCCCC{C}GGAAG. The deletion causes a frameshift starting with codon Arginine 516, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 43 of the new reading frame, denoted p.Arg516GlyfsX43. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation, as the last 95 amino acids are replaced with 42 incorrect amino acids. The variant is found in MEN1 panel(s).
Invitae RCV000228926 SCV000291287 pathogenic Multiple endocrine neoplasia, type 1 2018-12-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the MEN1 mRNA (c.1546delC), causing a frameshift at codon 516. This creates a premature translational stop signal in the last exon of the MEN1 mRNA (p.Arg516Glyfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MEN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals and families affected with multiple endocrine neoplasia type 1, or related disorders (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 23321498). It is considered to be a recurrent pathogenic mutation (PMID: 17879353). This variant is also known as 1650delC and 1656delC in the literature. ClinVar contains an entry for this variant (Variation ID: 200999). This variant truncates the functionally conserved nuclear localization signal of the MEN1 protein. Experimental studies have shown that disruption of this region abrogates the ability of MEN1 to bind DNA, regulate target gene expression, and inhibit cell proliferation (PMID: 15331604, 16449969). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000182439 SCV001144496 pathogenic not provided 2019-03-21 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000228926 SCV001160045 pathogenic Multiple endocrine neoplasia, type 1 2018-10-31 criteria provided, single submitter clinical testing The MEN1 c.1540delC; p.Arg516fs variant (rs794728642), also known as 1650delC or 1656delC, is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 1 (Agarwal 1997, Cardinal 2005, Cuny 2013, Ellard 2005, Giraud 1998, Schaaf 2007, Wautot 2002). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 200999), and is found in the Finnish European population with an allele frequency of 0.027% (5/18,304 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 43 amino acid residues not usually present. This variant is predicted to disrupt a nuclear localization signal, and similar disruptions have been shown to abrogate the ability for MEN1 protein to bind DNA and inhibit cell proliferation (La 2004). Based on available information, the p.Arg516fs 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. Cardinal JW et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005 Jan;42(1):69-74. Cuny T et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. Eur J Endocrinol. 2013 Mar 15;168(4):533-41. Ellard S et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005 Feb;62(2):169-75. Giraud S et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455-67. La P et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem. 2004 Nov 19;279(47):49045-54. 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. 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.
Ambry Genetics RCV001012050 SCV001172450 pathogenic Hereditary cancer-predisposing syndrome 2019-11-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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