rs753022747

Positions:

• chr11-64804626-G-A
• chr11-64804626-G-C
• chr11-64804626-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_001370259.2(MEN1):​c.1541C>T​(p.Pro514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P514?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.46

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64804625-GGG-GC 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28393906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1541C>T	p.Pro514Leu	missense_variant	10/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1541C>T	p.Pro514Leu	missense_variant	10/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454664 Hom.: 0 Cov.: 43 AF XY: 0.00000138 AC XY: 1 AN XY: 723552

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000509 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

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 not expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 457307). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 514 of the MEN1 protein (p.Pro514Leu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The p.P514L variant (also known as c.1541C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1541. The proline at codon 514 is replaced by leucine, an amino acid with similar properties. This alteration was detected in a patient with multiple endocrine neoplasia type 1 (MEN1); however, the patient was also positive for a second MEN1 alteration that was classified as pathogenic by the authors (Romanet P et al. J Clin Endocrinol Metab, 2019 03;104:753-764). 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	Benign	0.060
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;.;.;T;T;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.1	.;.;.;.;.;L;L;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.022	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B;B;B
Vest4		0.13
MutPred		0.40		.;.;.;.;.;Loss of glycosylation at P519 (P = 0.0163);Loss of glycosylation at P519 (P = 0.0163);Loss of glycosylation at P519 (P = 0.0163);Loss of glycosylation at P519 (P = 0.0163);
MVP		0.59
MPC		1.1
ClinPred		0.24	T
GERP RS		2.1
Varity_R		0.062
gMVP		0.43

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: rs753022747; hg19: chr11-64572098;