rs104894261
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.1579C>T(p.Arg527*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Consequence
MEN1
NM_001370259.2 stop_gained
NM_001370259.2 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.29
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 18 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 25 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-64804588-G-A is Pathogenic according to our data. Variant chr11-64804588-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804588-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MEN1 | NM_001370259.2 | c.1579C>T | p.Arg527* | stop_gained | 10/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 42
GnomAD4 exome
Cov.:
42
GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | MEN1: PVS1:Strong, PM2, PS4:Moderate, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 15, 2024 | PP1_moderate, PM2_moderate, PS3_moderate, PS4_moderate, PVS1_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 13, 2024 | This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is not expected to cause loss of protein expression through nonsense-mediated decay, however, similar variants in this region have been associated with disease, and therefore, this variant is also expected to contribute to disease. 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: 15331604) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 10, 2021 | The MEN1 c.1579C>T; p.Arg527Ter variant (rs104894261), also known as c.1594C>T; p.Arg532Ter in transcript NM_000244.3, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Carvalho 2018, Chandrasekharappa 1997, Hasani-Ranjbar 2014, Pardi 2017, Perrier 2002, Pieterman 2012). This variant has been observed to co-segregate with disease in affected members of several families (Hasani-Ranjbar 2014, Perrier 2002). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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 missing the last 84 amino acids. Based on available information, this variant is considered to be pathogenic. References: Carvalho RA et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur J Endocrinol. 2018 Dec 1;179(6):391-407. Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7. Hasani-Ranjbar S et al. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation. Fam Cancer. 2014 Jun;13(2):267-72. 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. Perrier ND et al. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2020 | Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17555499, 22470073, 24218143, 9103196, 27846313, 15082967, 12755956, 10709111, 12016470, 11579199, 9681840, 17823710, 9709921, 29036195, 30324798, 31414909) - |
Multiple endocrine neoplasia, type 1 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R527* in MEN1 (NM_130799.2) has been reported in previously affected patients (Pardi E et al, 2017). The p.R527* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Since it is present in the last exon,it may not cause nonsense mediated decay. However since has been reported in multiple affected patients and families (Pieterman CR etal,2012; Chung YJ e 2014;Kong J et al,2016) and there are presence of downstream truncating variants (Schaaf L et al,2007), the above variant has been classfied as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 08, 2023 | The c.1579C>T (p.Arg527*) variant in the MEN1 gene is predicted to result in an absent or truncated protein product. This variant has been reported in several individuals (>10) with multiple endocrine neoplasia type 1 (MEN1) or MEN1 related diseases (PMID: 9103196, 29036195, 25309785, 9709921, 22470073, 27846313, 29092957, 32761341, 30820182, 9681840, 11303512). This variant is reported to segregate with disease in two families (PMID: 24218143, 12016470). Loss of function variants of MEN1 are known to be pathogenic (PMID: 32780883, 31044390, 32430905). Truncating variants downstream of this variant are reported in individuals with MEN1 related phenotypes (PMID: 12112656, 15714081, 17853334). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 16688). Therefore, the c.1579C>T (p.Arg527*) variant in the MEN1 gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | This sequence change creates a premature translational stop signal (p.Arg527*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type I syndrome (MEN1) and MEN1-related disease (PMID: 9103196, 9709921, 22470073, 24218143, 25309785, 27846313, 29036195). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1594C>T (p.Arg532X) and c.1689C>T. ClinVar contains an entry for this variant (Variation ID: 16688). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 15331604, 16449969, 17853334). 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 | Apr 18, 1997 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 15, 2021 | The p.R527* pathogenic mutation (also known as c.1579C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1579. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of MEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been reported in multiple unrelated individuals affected with MEN1 syndrome (Chandrasekharappa S et al Science. 1997 Apr 18;276(5311):404-7; Chung YJ et al. Endocrinol Metab (Seoul). 2014 Sep;29:270-9; Pardi E et al. PLoS One. 2017 Oct;12:e0186485). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Neuroendocrine pancreatic tumor Other:1
| -, no assertion criteria provided | research | Genome Sciences Centre, British Columbia Cancer Agency | Nov 13, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at