11-64807902-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001370259.2(MEN1):c.643G>A(p.Val215Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V215E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.15

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr11-64807901-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3235101.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, MEN1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-64807902-C-T is Pathogenic according to our data. Variant chr11-64807902-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807902-C-T is described in Lovd as [Pathogenic]. Variant chr11-64807902-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.643G>A	p.Val215Met	missense_variant	3/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.643G>A	p.Val215Met	missense_variant	3/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 09, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the MEN1 protein (p.Val215Met). This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 10664520, 21464564, 25309785, 33632163). ClinVar contains an entry for this variant (Variation ID: 200977). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 11, 2023	The MEN1 c.643G>A (p.Val215Met) missense variant has been identified in several individuals with multiple endocrine neoplasia type 1 (PMID: 10664520; 15464422; 17879353; 25309785; 33632163). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Val215Met variant resides close to other clinically significant missense variants (ClinVar) and multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.643G>A (p.Val215Met) variant is classified as likely pathogenic for multiple endocrine neoplasia type 1. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.658G>A; p.(V220M); This variant is associated with the following publications: (PMID: 15464422, 10664520, 21464564, 29497973, 25309785, 17879353, 15714081, 33632163, 9989505) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.;D;D;D;D;D;.;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	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	0.72	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;D;.;T;T
Polyphen		1.0, 0.32	.;D;D;D;B;B;B;B;.;.;.
Vest4		0.50
MutPred		0.82		.;.;.;.;Gain of catalytic residue at V216 (P = 0.0584);Gain of catalytic residue at V216 (P = 0.0584);Gain of catalytic residue at V216 (P = 0.0584);Gain of catalytic residue at V216 (P = 0.0584);.;.;.;
MVP		0.93
MPC		1.5
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.36
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: 3
DS_DL_spliceai		0.58		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728621; hg19: chr11-64575374; COSMIC: COSV53641061; COSMIC: COSV53641061;