rs386134259

Positions:

• chr11-64807577-G-A
• chr11-64807577-G-C
• chr11-64807577-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001370259.2(MEN1):​c.758C>T​(p.Ser253Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,840 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. S253W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.97

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 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, 13 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 chr11-64807577-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 403831.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, 0.971
• PP5: Variant 11-64807577-G-A is Pathogenic according to our data. Variant chr11-64807577-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201012.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=2, Uncertain_significance=1}. Variant chr11-64807577-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.758C>T	p.Ser253Leu	missense_variant	4/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.758C>T	p.Ser253Leu	missense_variant	4/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 253 of the MEN1 protein (p.Ser253Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 17623761, 20660572; Invitae). ClinVar contains an entry for this variant (Variation ID: 201012). 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%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 21819486). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	Apr 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 21, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2022

Published functional studies demonstrate a damaging effect: decreased protein expression and stability (Shimazu 2011); Observed in individuals with MEN1-related tumors referred for testing at GeneDx and in published literature (Tham 2007, Erlic 2010, Raj 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.868C>T; p.S258L; This variant is associated with the following publications: (PMID: 10931084, 17623761, 17065424, 17879353, 20660572, 24265153, 26269718, 30687805, 30869828, 12874027, 21819486) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The p.S253L variant (also known as c.758C>T), located in coding exon 3 of the MEN1 gene, results from a C to T substitution at nucleotide position 758. The serine at codon 253 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MEN1-related disease (Ambry internal data). This alteration has also been reported in two unrelated families with hyperparathyroidism (HPT) (Tham E et al. J Clin Endocrinol Metab. 2007 Sep;92(9):3389-95; Potorac I et al. Annales d'Endocrinologie 2015 Sept;76(4) 486) and in an affected German patient listed in the international Neuroendocrine Tumor Registry (Erlic Z et al Endocr Relat Cancer. 2010 Oct 5;17(4):875-83). Based on internal structural analysis, this alteration is anticipated to destabilize the structure of menin (Murai MJ et al. J. Biol. Chem., 2011 Sep;286:31742-8; Huang J et al. Nature, 2012 Feb;482:542-6). 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	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;D;D;D;D;D;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.014	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;T;T;T;T;T;.;T;T
Polyphen		1.0, 1.0	.;D;D;D;D;D;D;D;D;.;.;.
Vest4		0.87
MutPred		0.89		.;.;.;.;.;Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);.;.;.;
MVP		1.0
MPC		1.9
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.68
gMVP		0.96

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: rs386134259; hg19: chr11-64575049; COSMIC: COSV53641504; COSMIC: COSV53641504;