rs200035619

chr11-64804788-C-Gchr11-64804788-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001370259.2(MEN1):c.1379G>C(p.Arg460Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R460Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MEN1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1379G>C	p.Arg460Pro	missense_variant	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1379G>C	p.Arg460Pro	missense_variant	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 34

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	Baylor Genetics	Jun 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2023	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 460 of the MEN1 protein (p.Arg460Pro). This variant is not present in population databases (gnomAD no frequency). 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: 403834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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

Mar 09, 2023

The p.R460P variant (also known as c.1379G>C), located in coding exon 9 of the MEN1 gene, results from a G to C substitution at nucleotide position 1379. The arginine at codon 460 is replaced by proline, an amino acid with dissimilar 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	Benign	0.22
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.;.;D;D;D;D
Eigen	Benign	0.022
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.012	D;T;T;T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T
Polyphen		0.69, 0.73	.;P;P;P;P;P;P;P;P
Vest4		0.34
MutPred		0.67		.;.;.;.;.;Loss of MoRF binding (P = 0.0104);Loss of MoRF binding (P = 0.0104);Loss of MoRF binding (P = 0.0104);Loss of MoRF binding (P = 0.0104);
MVP		0.85
MPC		2.6
ClinPred		0.75	D
GERP RS		4.5
Varity_R		0.16
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

Other links and lift over

dbSNP: rs200035619; hg19: chr11-64572260;