11-64805742-TCTC-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_001370259.2(MEN1):c.1075_1077delGAG(p.Glu359del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 conservative_inframe_deletion
NM_001370259.2 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.25
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001370259.2. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MEN1 | NM_001370259.2 | c.1075_1077delGAG | p.Glu359del | conservative_inframe_deletion | Exon 8 of 10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 01, 2024 | This variant, c.1075_1077del, results in the deletion of 1 amino acid(s) of the MEN1 protein (p.Glu359del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with parathyroid tumors and pancreatic gastrinoma (PMID: 9463336). ClinVar contains an entry for this variant (Variation ID: 403799). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Mar 28, 2018 | The MEN1 variant designated as NM_130799.2:c.1075_1077del (p.Glu359del) is classified as benign. In one observed family, multiple family members with the variant are unaffected by the multiple endocrine neoplasia constellation of symptoms, while one individual with a MEN1-associated cancer does not have the variant. Cosegregation analysis of this same observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.0001 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:12900794). This likelihood ratio indicates strong evidence against pathogenicity as the variant does not co-segregate with reported multiple endocrine neoplasia symptoms in this family. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives a <0.1% probability of pathogenicity, which is consistent with a classification of benign. This variant is not predicted to alter MEN1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at