11-64804620-CG-CGG
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001370259.2(MEN1):c.1546dupC(p.Arg516fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,455,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 frameshift
NM_001370259.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.09
Genes affected
MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
PP5
Variant 11-64804620-C-CG is Pathogenic according to our data. Variant chr11-64804620-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 279852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MEN1 | NM_001370259.2 | c.1546dupC | p.Arg516fs | frameshift_variant | 10/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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34
GnomAD4 exome AF: 0.00000893 AC: 13AN: 1455540Hom.: 0 Cov.: 42 AF XY: 0.00000967 AC XY: 7AN XY: 724062
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GnomAD4 genome
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34
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This variant inserts 1 nucleotide in exon 10 of the MEN1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1650insC, 1657insC, and c.1546_1547insC in the literature. While this variant is not expected to trigger nonsense-mediated decay, the truncated protein is expected to disrupt that C-terminus that interacts with different proteins and also contain a nuclear localization domain (PMID: 17879353). Similar truncation variants have been reported as disease-causing in ClinVar, suggesting that the C-terminus of MEN1 is important for function (variation ID: 201002, 200986, 200999, 988375, 988490, 988531). This variant is a common variant and has been proposed to be a mutation hotspot because it has been reported in dozens of individuals and families affected with MEN1 from different populations worldwide (PMID: 9215689, 9463336, 11579199, 11303512, 12112656, 15240620, 15635078, 17853334, 17623761, 17879353, 20833329, 32299109, 34160414, 35696052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2022 | Variant summary: MEN1 c.1546dupC (p.Arg516ProfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.1e-05 in 237028 control chromosomes. c.1546dupC has been reported in the literature as a common pathogenic mutation in numerous individuals affected with Multiple Endocrine Neoplasia Type 1 and was shown to segregate with disease (examples: Kytola_2001, Bassett_1998, Romanet_2019, etc). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg516Profs*15) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the MEN1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689, 15635078, 21340156, 22470073, 24915123, 25291050). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1650insC, c.1561dup (p.Arg521fs), c.1561dupC, and c.1546dupC.. ClinVar contains an entry for this variant (Variation ID: 279852). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Arg516Glyfs*43) have been determined to be pathogenic (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 23321498). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 11, 2019 | The p.Arg521fs (as known as p.Arg516fs on transcript NM_130799.2) variant in MEN1 has been reported in >20 individuals with familial hyperparathyroidism or multiple endocrine neoplasia type 1 and segregated in >5 affected individuals from 1 Finnish family (The 1998, Kytola 2001, Warner 2004, de Laat 2014, Pieterman 2012). This variant has been reported in ClinVar (Variation ID# 279852) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 521 and leads to a premature termination codon 15 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for multiple endocrine neoplasia type 1 in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PVS1_Strong, PM2, PP1_Moderate. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2022 | Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: impaired nuclear localization of protein compared to wild-type (Ikeo 1999); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1561dup, c.1650insC, c.1657insC, and c.7773insC; This variant is associated with the following publications: (PMID: 9463336, 11836268, 20660572, 28701629, 9361035, 10993647, 17879353, 17065424, 15714081, 12652570, 10576763, 10812010, 10849016, 9709921, 12050235, 14985373, 11058905, 11524904, 15670192, 12112656, 9747036, 21340156, 27038812, 11034102, 15240620, 11303512, 19041010, 25291050, 9215689, 15635078, 9683585, 15730416, 22470073, 29036195, 30324798, 20367983, 12213668, 17853334, 23321498, 24915123, 10595737, 34160414) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 17, 2024 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10595737) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 18, 2023 | This frameshift variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. In the published literature, the variant has been reported in affected individuals with multiple endocrine neoplasia type 1 in the published literature (PMIDs: 9215689 (1997), 12112656 (2002), 15670192 (2005), 17853334 (2007), 31482957 (2019), and 32909176 (2021)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2023 | The MEN1 c.1546dup; p.Arg516ProfsTer15 variant (rs767319284), also known as 1561dupC, 1650insC, 1656dupC, or 1657insC, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Cardinal 2005, de Laat 2014, Ebeling 2004, Karageorgiadis 2015, Kytola 2001, Pieterman 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 279852). 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, and other downstream pathogenic truncating variants have been reported in families with multiple endocrine neoplasia type 1 (Cardinal 2005, Pieterman 2012). Based on available information, this variant is considered to be pathogenic. References: 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. PMID: 15635078. de Laat JM et al. Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. J Clin Endocrinol Metab. 2014 Sep;99(9):3325-33. PMID: 24915123. Ebeling T et al. Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations. J Clin Endocrinol Metab. 2004 Jul;89(7):3392-6. Karageorgiadis AS et al. Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. J Clin Endocrinol Metab. 2015 Jan;100(1):141-8. PMID: 15240620. Kytola S et al. Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. J Med Genet. 2001 Mar;38(3):185-9. PMID: 11303512. Pieterman CR et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg. 2012 Jun;255(6):1171-8. PMID: 22470073. - |
Lung carcinoid tumor Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1997 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2023 | The c.1546dupC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of C at nucleotide position 1546, causing a translational frameshift with a predicted alternate stop codon (p.R516Pfs*15). This mutation has been reported in several families affected with multiple endocrine neoplasia type 1 (MEN1) (Zha BB et al. Chinese Med J. 2010;123(5):569-573; Pieterman CR et al. Ann Surg. 2012 Jun;255(6):1171-8; Cardinal JW et al. J. Med. Genet., 2005 Jan;42:69-74; Pardi E et al. PLoS ONE. 2017 Oct;12(10):e0186485). This mutation was also reported in an early onset sporadic case of MEN1 (Boguszewski CL et al. Arq Bras Endocrinol Metabol. 2010 Nov;54(8):705-10) and in a patient with primary hyperparathyroidism (Lemos MC & Thakker RV Hum. Mutat. 2008 Jan; 29(1):22-32). Of note, this mutation is also designated as c.1546_1547insC, p.Arg521fsX15, and c.1561dup (p.Arg521fs) in the published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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