rs386134249
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001370259.2(MEN1):c.1262G>A(p.Cys421Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 6.83
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.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001370259.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MEN1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant 11-64805122-C-T is Pathogenic according to our data. Variant chr11-64805122-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805122-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1262G>A | p.Cys421Tyr | missense_variant | 9/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.1262G>A | p.Cys421Tyr | missense_variant | 9/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461832Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 exome
AF:
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1
AN:
1461832
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Cov.:
55
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AC XY:
1
AN XY:
727210
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 421 of the MEN1 protein (p.Cys421Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MEN1-related conditions (PMID: 15714081; Invitae). ClinVar contains an entry for this variant (Variation ID: 36523). 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. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17039269, 15714081, 17879353, 9989505, 34183184, 35428475) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 07, 2017 | The MEN1 c.1262G>A;p.Cys421Tyr variant has been published in the literature in one individual with a clinical diagnosis of MEN1 (Klein 2005). Additionally, ARUP laboratories has detected this variant in an individual with a clinical diagnosis of MEN1. The variant is listed in the dbSNP variant database (rs386134249) and the ClinVar database (Variation ID: 36523), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The cysteine at position 421 is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Taken together, this variant is considered likely pathogenic. References: Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 7(2):131-8. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2019 | The p.C421Y variant (also known as c.1262G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1262. The cysteine at codon 421 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in a series of patient samples submitted for MEN1 gene sequencing, and was presumed to be pathogenic due to its absence in 200 unaffected individuals, alteration of highly conserved base-pairs, and/or segregation within a family (Klein RD et al., Genet. Med. 2005 Feb; 7(2):131-8). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
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
0.87
.;.;.;.;Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);
MVP
MPC
2.8
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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