Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_001370259.2(MEN1):c.1739delC(p.Thr580ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T580T) has been classified as Likely benign.
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]
Our verdict: Likely_pathogenic. The variant received 8 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 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-64804427-CG-C is Pathogenic according to our data. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64804427-CG-C is described in CliVar as Likely_pathogenic. Clinvar id is 220647.Status of the report is criteria_provided_single_submitter, 1 stars.
This sequence change deletes 1 nucleotide from exon 10 of the MEN1 mRNA (c.1739delC), causing a frameshift at codon 580. This creates a premature translational stop signal in the last exon of the MEN1 mRNA (p.Thr580Argfs*8). 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) and has not been reported in the literature. This frameshift change truncates the functionally conserved NLS2 domain 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). In summary, this is a novel frameshift variant that truncates an important functional domain in MEN1. For these reasons, it has been classified as a Likely Pathogenic. -