rs398124435

Variant names:

• chr11-64805076-C-A
• rs398124435
• NM_001370259.2:c.1308G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1308G>T​(p.Trp436Cys) 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. W436R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.05
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 19 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 chr11-64805078-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-64805076-C-A is Pathogenic according to our data. Variant chr11-64805076-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1308G>T	p.Trp436Cys	missense_variant	Exon 9 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1308G>T	p.Trp436Cys	missense_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 34

Alfa AF: 0.000755 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 436 of the MEN1 protein (p.Trp436Cys). 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: 15714081; internal data). ClinVar contains an entry for this variant (Variation ID: 96250). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 22090276). This variant disrupts the p.Trp436 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9103196, 21127195, 21819486). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 06, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 31, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes the MEN1 gene product to be rapidly cleared by proteasomal degradation (PMID: 22090276). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W436C pathogenic mutation (also known as c.1308G>T), located in coding exon 8 of the MEN1 gene, results from a G to T substitution at nucleotide position 1308. The tryptophan at codon 436 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with Multiple endocrine neoplasia type 1 (MEN1) (Klein RD et al. Genet Med. 2005 Feb;7(2):131-8; Ambry internal data). The authors of one functional study suggested that the W436C mutant protein was targeted for rapid degradation based on low levels of expression compared to wild type menin (Canaff L. et al. J. Clin. Endocrinol. Metab. 2012 Feb;97(2):E282-91). Based on internal structural analysis, the W436 residue is buried and this alteration is anticipated to result in a significant decrease in structural stability (Huang J et al. Nature. 2012 Feb 12;482(7386):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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;M;M;M
PhyloP100		5.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.96
MutPred		0.89		.;.;.;.;Loss of MoRF binding (P = 0.0441);Loss of MoRF binding (P = 0.0441);Loss of MoRF binding (P = 0.0441);Loss of MoRF binding (P = 0.0441);
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398124435; hg19: chr11-64572548;