11-64805078-A-T

Variant names:

• chr11-64805078-A-T
• rs104894259
• NM_001370259.2:c.1306T>A

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1306T>A​(p.Trp436Arg) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W436C) has been classified as 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: 6.14

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 21 ACMG points.

• PS1: Transcript NM_001370259.2 (MEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64805076-C-A is described in Lovd as [Pathogenic].
• 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, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-64805078-A-T is Pathogenic according to our data. Variant chr11-64805078-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16686.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.1306T>A	p.Trp436Arg	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.1306T>A	p.Trp436Arg	missense_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 34

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:3

Apr 18, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. A different variant (c.1306T>C) giving rise to the same protein effect observed here (p.Trp436Arg) has been reported in individuals affected with multiple endocrine neoplasia type 1 (PMID: 9103196, 15714081), indicating that this residue may be critical for protein function. The p.Trp436Arg substitution has been shown to reduce the expression of menin protein in vitro (PMID: 21819486). In addition, it interferes with the interaction between menin and AKT1 kinase thereby disrupts ATK1-mediated anti-apoptosis effect in endocrine cells (PMID: 21127195) This variant has been reported in an individual affected with multiple endocrine neoplasia type 1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 16686). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 436 of the MEN1 protein (p.Trp436Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -

Jul 26, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9540988, 9103196, 15714081, 9498491]. Functional studies indicate this variant impacts protein function [PMID: 21127195, 21819486]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1

Dec 15, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W436R variant has previously been reported in at least one individual undergoing genetic testing of the MEN1 gene at an outside clinical laboratory (Klein et al., 2005). Functional studies have shown that the W436R mutant protein is not stable and is rapidly degraded by the ubiquitin-proteasome pathway (Canaff et al., 2012). This variant is not observed in large population cohorts (Lek et al., 2016). The XW436R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. An alternate nucleotide change resulting in the same amino acid change (c.1306T>C) has been reported in association with multiple endocrine neoplasia type 1, supporting the functional importance of this region of the protein (Agarwal et al., 1997; Chandrasekharappa et al., 1997). Based on the currently available information, we consider W436R to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W436R pathogenic mutation (also known as c.1306T>A), located in coding exon 8 of the MEN1 gene, results from a T to A substitution at nucleotide position 1306. The tryptophan at codon 436 is replaced by arginine, an amino acid with dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with MEN1-associated disease (Ambry internal data). In one study, the p.W436R variant failed to interact with ATK1 and was unable to suppress AKT1 activity (Wang Y et al. Cancer Res, 2011 Jan;71:371-82). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data). Another variant resulting in the same amino acid substitution, p.W436R (c.1306T>C), has been described in patients with MEN1-associated disease (Chandrasekharappa SC et al. Science.1997. 276(5311):404-7) and was shown to induce a high rate of protein degradation and roughly 20% stability when compared to wild types (Shimazu et al. Cancer Science. 2011. Vol 102, No 11, 2097-2102). 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 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	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.84	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
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-12	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	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.98
MutPred		0.88		.;.;.;.;Gain of methylation at W441 (P = 0.0165);Gain of methylation at W441 (P = 0.0165);Gain of methylation at W441 (P = 0.0165);Gain of methylation at W441 (P = 0.0165);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894259; hg19: chr11-64572550;