rs863224810

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_001370259.2(MEN1):c.1354C>T(p.Arg452Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,596,730 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R452P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 4.47

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 Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_001370259.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64804813-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2987184.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, MEN1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 11-64804813-G-A is Pathogenic according to our data. Variant chr11-64804813-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216815.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1354C>T	p.Arg452Trp	missense_variant	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1354C>T	p.Arg452Trp	missense_variant	10/10	5	NM_001370259.2	P3	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718700

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Pathogenic:1Uncertain:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 452 of the MEN1 protein (p.Arg452Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 29036195; Invitae). ClinVar contains an entry for this variant (Variation ID: 216815). 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%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 26, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely pathogenic and reported on 08-18-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 14, 2023

The MEN1 c.1354C>T; p.Arg452Trp variant (rs863224810) is reported in individuals affected with familial multiple endocrine neoplasia, type 1 (Pardi 2017, ARUP internal data). This variant is also reported in ClinVar (Variation ID: 216815), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.961). Based on available information, this variant is considered to be likely pathogenic. References: Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. PMID: 29036195. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2022

The p.R452W variant (also known as c.1354C>T) is located in coding exon 9 of the MEN1 gene. This alteration results from a C to T substitution at nucleotide position 1354. The arginine at codon 452 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple families with clinical features of MEN1 (Pardi E et al. PLoS ONE 2017 Oct;12(10):e0186485; Ambry internal data). Structural analysis demonstrates that the total energy of p.R452W is considerably higher compared to the native structure, implying a possible underlying damaging effect on protein structure, potentially affecting protein stability and function (Shi A et al. Blood, 2012 Nov;120:4461-9; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.;.;D;D;D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

0.99

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

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

N;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.65

MutPred

0.83

.;.;.;.;.;Loss of disorder (P = 0.0289);Loss of disorder (P = 0.0289);Loss of disorder (P = 0.0289);Loss of disorder (P = 0.0289);

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

4.5

Varity_R

0.85

gMVP

1.0

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