11-64810034-C-T

Variant names:

• chr11-64810034-C-T
• rs28931612
• NM_001370259.2:c.76G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001370259.2(MEN1):​c.76G>A​(p.Glu26Lys) variant causes a missense 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.13
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 31 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 11-64810034-C-T is Pathogenic according to our data. Variant chr11-64810034-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.76G>A	p.Glu26Lys	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.76G>A	p.Glu26Lys	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parathyroid adenoma, somatic Pathogenic:1

Aug 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple endocrine neoplasia, type 1 Pathogenic:1

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as G186A (E26K). ClinVar contains an entry for this variant (Variation ID: 16689). 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. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 9820618, 12016472, 20231234; Invitae). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 26 of the MEN1 protein (p.Glu26Lys). This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:1

Nov 13, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in patients with personal and/or family histories consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Bartsch 1998, Langer 2002, Ellard 2005, Schaff 2007, Waldmann 2007, Schaefer 2008, White 2010); This variant is associated with the following publications: (PMID: 9241276, 9820618, 11114630, 15670192, 17853334, 17235589, 20231234, 30869828, 18426829, 12016472, 10730900) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M;M;M;M;M;M;M;M;.;.;.;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D;T;T;T;D;D
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen		1.0, 0.95, 0.96	.;D;P;P;P;D;D;D;D;.;.;.;.;.
Vest4		0.76
MutPred		0.80		Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);Gain of ubiquitination at E26 (P = 0.0238);
MVP		0.99
MPC		1.9
ClinPred		0.96	D
GERP RS		4.9
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28931612; hg19: chr11-64577506; COSMIC: COSV56343608;