11-64806250-G-A

Position:

chr11-64806250-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM2PM5PP2PP3BS2

The NM_001370259.2(MEN1):c.1031C>T(p.Thr344Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64806250-G-C 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, 0.745

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1031C>T	p.Thr344Met	missense_variant	7/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1031C>T	p.Thr344Met	missense_variant	7/10	5	NM_001370259.2	ENSP00000394933	P3	O00255-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251438

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 344 of the MEN1 protein (p.Thr344Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 527269). 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 with a positive predictive value of 95%. This variant disrupts the p.Thr344 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 9215689, 29036195), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.T344M variant (also known as c.1031C>T), located in coding exon 6 of the MEN1 gene, results from a C to T substitution at nucleotide position 1031. The threonine at codon 344 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.;.;D;D;D;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;.;D;.;.;D;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.74

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.1

.;.;.;.;.;L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;.

Polyphen

0.98, 1.0

.;D;D;D;D;D;D;D;D;.

Vest4

0.72

MutPred

0.43

.;.;.;.;.;Gain of catalytic residue at T349 (P = 0.0119);Gain of catalytic residue at T349 (P = 0.0119);Gain of catalytic residue at T349 (P = 0.0119);Gain of catalytic residue at T349 (P = 0.0119);.;

MVP

0.86

MPC

2.1

ClinPred

0.92

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.59

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over