chr11-64807916-G-T

Position:

• chr11-64807916-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.629C>A​(p.Thr210Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.90

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.629C>A	p.Thr210Lys	missense_variant	3/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.629C>A	p.Thr210Lys	missense_variant	3/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2022	ClinVar contains an entry for this variant (Variation ID: 1480061). 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. 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 has not been reported in the literature in individuals affected with MEN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 210 of the MEN1 protein (p.Thr210Lys). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2024	This missense variant replaces threonine with lysine at codon 210 of the MEN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MEN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The p.T210K variant (also known as c.629C>A), located in coding exon 2 of the MEN1 gene, results from a C to A substitution at nucleotide position 629. The threonine at codon 210 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.85
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.;.;.;D;D;D;D;D;.;D
Eigen	Benign	-0.026
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.3	.;.;.;.;L;L;L;L;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.78	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.015, 0.019	.;B;B;B;B;B;B;B;.;.;.
Vest4		0.66
MutPred		0.64		.;.;.;.;Gain of catalytic residue at T215 (P = 0.01);Gain of catalytic residue at T215 (P = 0.01);Gain of catalytic residue at T215 (P = 0.01);Gain of catalytic residue at T215 (P = 0.01);.;.;.;
MVP		0.98
MPC		1.3
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64575388;