MEN1

Chr 11AD

menin 1

Also known as: MEAI, SCG2

NCBI Gene: 4221 ENSG00000133895 UniProt: O00255

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]

Primary Disease Associations & Inheritance

Adrenal adenoma, somatic

Angiofibroma, somatic

Carcinoid tumor of lung

Lipoma, somatic

Multiple endocrine neoplasia 1MIM #131100

Parathyroid adenoma, somatic

Multiple endocrine neoplasia 1MIM #131100

UniProtFamilial multiple endocrine neoplasia type I

700

ClinVar variants

141

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— MEN1

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Gene-Disease Validity (ClinGen)

multiple endocrine neoplasia type 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

141 Pathogenic / Likely Pathogenic· 297 VUS of 700 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.17LOEUF

pLI 1.000

Z-score 4.71

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.25Z-score

OE missense 0.53 (0.47–0.59)

200 obs / 377.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.17)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.53 (0.47–0.59)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93

0≤1.21.6

LoF obs/exp: 1 / 27.8Missense obs/exp: 200 / 377.7Syn Z: 0.75

ClinVar Variant Classifications

700 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic95

Likely Pathogenic46

VUS297

Likely Benign189

Benign50

Conflicting23

Pathogenic

Likely Pathogenic

297

VUS

189

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	65	4	26	0	95
Likely Pathogenic	19	19	8	0	46
VUS	6	267	20	4	297
Likely Benign	0	3	66	120	189
Benign	0	1	28	21	50
Conflicting	—				23
Total	90	294	148	145	700

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MEN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MEN1-related multiple endocrine neoplasia

definitive

ADLoss Of FunctionAbsent Gene Product

SkinCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

MENIN 1 ; MEN1

MIM #613733 · *

Adrenal adenoma, somatic