rs587776841
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.249_252delGTCT(p.Ile85fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 frameshift
NM_001370259.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.57
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-64809857-TAGAC-T is Pathogenic according to our data. Variant chr11-64809857-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 16693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809857-TAGAC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MEN1 | NM_001370259.2 | c.249_252delGTCT | p.Ile85fs | frameshift_variant | 2/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1458904Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 725592
GnomAD4 exome
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GnomAD4 genome
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Cov.:
30
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 | Baylor Genetics | Nov 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2022 | Variant summary: MEN1 c.249_252delGTCT (p.Ile85SerfsX33) 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 was absent in 240006 control chromosomes (gnomAD). c.249_252delGTCT has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (e.g. Bassett_1998, Geerdink_2003, Wautot_2002). The variant was found in about 4.5% of all Multiple Endocrine Neoplasia Type 1 patients/families (Lemos_2008). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 21, 2016 | The p.Ile85fs variant in MEN1 has been reported in multiple individuals with mul tiple endocrine neoplasia type 1 and segregated with disease in affected relativ es (Lemmens 1997, Lemos 2008). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino ac id sequence beginning at codon 85 and leads to a premature termination codon 33 amino acids downstream. Heterozygous loss-of-function is an established disease mechanism in multiple endocrine neoplasia type 1. In summary, this variant meets our criteria to be classified as pathogenic for multiple endocrine neoplasia ty pe 1 in an autosomal dominant manner. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ile85Serfs*33) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9103196, 9215690, 15635078, 17623761, 17879353, 24915123). ClinVar contains an entry for this variant (Variation ID: 16693). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 18, 1997 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 31, 2020 | 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 patient with expected phenotype for this gene, and not found in general population data. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 05, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 30, 2024 | The MEN1 c.249_252del (p.Ile85Serfs*33) variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. This variant has been reported in the published literature in several individuals with multiple endocrine neoplasia type 1 (MEN1) syndrome (PMIDs: 9103196 (1997), 9683585 (1998), 9671267 (1998), 9463336 (1998), 10576763 (1999), 10594843 (1999), 10664520 (2000), 15635078 (2005), 17623761 (2007), 17953629 (2007), 18045958 (2007), 27572829 (2016), 28968916 (2017), 29036195 (2017), 30324798 (2018), 35448982 (2022), 35965945 (2022), 35668420 (2022), 37484956 (2023)). This variant has also been reported in an individual with breast and thyroid cancer (PMID: 35534704 (2022)) and in an individual with MEN1 along with tumors in atypical-related organs of liver and lung (PMID: 35538538 (2022)). In addition, this variant was found in about 4.5% of all unrelated MEN1 families from a review of around 1133 variants identified in MEN1 gene (PMID: 17879353 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Present in up to 4.5% of families with MEN1 (Lemos 2008); Also known as 249del4, 357del4, and 359del4; This variant is associated with the following publications: (PMID: 24915123, 29395620, 28130400, 28597079, 29036195, 27572829, 17879353, 32937789, 10856877, 9103196, 26767918, 24599222, 23093699, 19461164, 22740705, 17623761, 9709921, 17853334, 15281352, 9888389, 10617276, 9215689, 9671267, 10720085, 28870973, 30324798, 28968916, 30795813, 30339208) - |
Lipoma, somatic Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 04, 1998 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2024 | The c.249_252delGTCT pathogenic mutation, located in coding exon 1 of the MEN1 gene, results from a deletion of 4 nucleotides at nucleotide positions 249 to 252, causing a translational frameshift with a predicted alternate stop codon (p.I85Sfs*33). This alteration has been detected in multiple unrelated families in which the proband and/or family members exhibited the following MEN1-related characteristics: hyperparathyroidism, pituitary tumors, endocrine pancreatic tumors, carcinoid tumors, as well as a gastrinoma (Cardinal JW et al. J. Med. Genet. 2005 Jan;42(1):69-74). Another study found this alteration in a large kindred with familial isolated hyperparathyroidism and no other symptoms of MEN1 (Karges W et al. J. Endocrinol. 2000 Jul;166:1-9). This alteration has also been detected in an individual who presented at five years of age with hyperinsulinaemic hypoglycemia due to an insulinoma; he was subsequently monitored for other signs of MEN1 syndrome and, five years following his initial diagnosis, was found to have parathyroid adenoma (Padidela R et al. Eur. J. Endocrinol. 2014 May;170:741-7). In a review of the over 1300 mutations identified in the MEN1 gene since its discovery in 1997, this frameshift mutation was found to be in 4.5% of unrelated MEN1 families (Lemos MC and Thakker RV. Human Mutation. 2008 Jan;29(1):22-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
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