rs398124435
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_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 Pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 5.05
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
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 Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, 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 [Likely_pathogenic]. Clinvar id is 96250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805076-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1308G>T | p.Trp436Cys | missense_variant | 9/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.1308G>T | p.Trp436Cys | missense_variant | 9/10 | 5 | NM_001370259.2 | ENSP00000394933.3 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 42
GnomAD4 exome
Cov.:
42
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 28, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects MEN1 function (PMID: 22090276). 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. ClinVar contains an entry for this variant (Variation ID: 96250). This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 15714081; Invitae). This variant is not present in population databases (gnomAD no frequency). 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 19, 2021 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2018 | The p.W436C (also known as c.1308G>T) pathogenic mutation is located in coding exon 8 of the MEN1 gene. This alteration 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 alteration has been identified in an individual with suspected MEN1 (Klein RD et al. Genet Med. 2005 Feb;7(2):131-8). 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). In addition, a second missense mutation at this codon (p.W436R) has also been described (Chandrasekharappa SC et al. Science.1997. 276(5311):404-7). Based on the evidence available to date, this alteration is classified as a pathogenic mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;.;D;.;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;M;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D
Vest4
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
MPC
2.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at