rs863224807
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_001370259.2(MEN1):c.1063C>T(p.Arg355Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,822 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 6.66
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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. GenCC has associacion of the gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943
PP5
Variant 11-64805757-G-A is Pathogenic according to our data. Variant chr11-64805757-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527242.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr11-64805757-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1063C>T | p.Arg355Trp | missense_variant | 8/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 exome
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1461822
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32
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1
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727212
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 10, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 527242). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 15714081, 30820182). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the MEN1 protein (p.Arg355Trp). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Strong+PS4_Supporting - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2024 | The p.R355W variant (also known as c.1063C>T), located in coding exon 7 of the MEN1 gene, results from a C to T substitution at nucleotide position 1063. The arginine at codon 355 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in an individual suspicious for multiple endocrine neoplasia type 1 (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 available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;.;D;.;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;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;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;D;D;D;D;D
Vest4
MutPred
0.77
.;.;.;.;.;Gain of catalytic residue at R360 (P = 0.0188);Gain of catalytic residue at R360 (P = 0.0188);Gain of catalytic residue at R360 (P = 0.0188);Gain of catalytic residue at R360 (P = 0.0188);
MVP
MPC
2.3
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