rs863224526

chr11-64804738-C-Achr11-64804738-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):c.1429G>T(p.Glu477Ter) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.27

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]

ACMG classification

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 76 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804738-C-A is Pathogenic according to our data. Variant chr11-64804738-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 216133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804738-C-A is described in Lovd as [Pathogenic]. Variant chr11-64804738-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1429G>T	p.Glu477Ter	stop_gained	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1429G>T	p.Glu477Ter	stop_gained	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 07, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: MEN1 c.1429G>T (p.Glu477X) 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 225462 control chromosomes. c.1429G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (eg. Cote_1998, Dackiw_1999, Klein_2005, Kouvaraki_2002, etc). Four 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	Invitae	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Glu477*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 134 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 individual(s) with multiple endocrine neoplasia 1 (MEN1) (PMID: 12049533, 15714081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216133). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation (PMID: 15331604, 16449969). While functional studies have not been performed to directly test the effect of this variant on MEN1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 28, 2019	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2023	The MEN1 c.1429G>T; p.Glu477Ter variant (rs863224526) is reported in the medical literature in individuals and families with a clinical diagnosis of multiple endocrine neoplasia type 1 (Dackiw 1999, Klein 2005, Kouvaraki 2002). The variant is described as pathogenic in the ClinVar database (Variation ID: 216133) and is absent from the 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. Considering available information, this variant is classified as pathogenic. References: Dackiw AP et al. Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Surgery. 1999 Dec;126(6):1097-103. PMID: 10598193. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID: 15714081. Kouvaraki MA et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg. 2002 Jun;137(6):641-7. PMID: 12049533. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 28, 2021	This nonsense variant causes the premature termination of MEN1 protein synthesis. In addition, it has been reported in symptomatic individuals with multiple endocrine neoplasia 1 in the published literature (PMIDs: 12049533 (2002) and 15714081 (2005)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2022	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 (gnomAD); Identified in patients with multiple endocrine neoplasia type 1 referred for genetic testing at this laboratory and in published literature (Cote 1998, Dackiw 1999, Kouvaraki 2002, Klein 2005); This variant is associated with the following publications: (PMID: 15714081, 17879353, 12049533, 10660339, 10598193, 15281352) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The p.E477* pathogenic mutation (also known as c.1429G>T), located in coding exon 9 of the MEN1 gene, results from a G to T substitution at nucleotide position 1429. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 134 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 mutation has been detected in seven affected members of one family (Kouvaraki MA et al. Arch Surg. 2002 Jun;137(6):641-7). In addition to the clinical data presented in the literature, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.78
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224526; hg19: chr11-64572210;