rs1114167491

Positions:

• chr11-64809977-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.133G>A​(p.Glu45Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E45A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.58

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]

MEN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64809976-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 11-64809977-C-T is Pathogenic according to our data. Variant chr11-64809977-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809977-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.133G>A	p.Glu45Lys	missense_variant	2/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.133G>A	p.Glu45Lys	missense_variant	2/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2021

This variant has been observed in individual(s) with a personal and/or family history of MEN1-related conditions (PMID: 10664520, 17623761, 29239255). It has also been observed to segregate with disease in related individuals (PMID: 12746426, 12166655). ClinVar contains an entry for this variant (Variation ID: 428029). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 45 of the MEN1 protein (p.Glu45Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2020

The p.E45K pathogenic mutation (also known as c.133G>A), located in coding exon 1 of the MEN1 gene, results from a G to A substitution at nucleotide position 133. The glutamic acid at codon 45 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in multiple patients with MEN1 (Morelli A et al. Eur. J. Endocrinol., 2000 Feb;142:131-7; Arancha C et al. J. Hum. Genet., 2002;47:190-5; Tham E et al. J. Clin. Endocrinol. Metab., 2007 Sep;92:3389-95). It has also been observed to segregate with disease in three affected individuals from a Spanish MEN1 family whose clinical features included parathyroid, anterior pituitary, and enteropancreatic lesions (Cebrián A et al. J. Med. Genet., 2003 May;40:e72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.015, 1.0	.;B;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.74
MutPred		0.93		Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);Gain of methylation at E45 (P = 0.0172);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1114167491; hg19: chr11-64577449;