rs1064793169
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001370259.2(MEN1):c.922T>C(p.Ser308Pro) 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 (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 4.11
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 15 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 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, 0.922
PP5
?
Variant 11-64806359-A-G is Pathogenic according to our data. Variant chr11-64806359-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.922T>C | p.Ser308Pro | missense_variant | 7/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.922T>C | p.Ser308Pro | missense_variant | 7/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2016 | The S308P variant in the MEN1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S308P 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. This substitution occurs at a position that is conserved across species, and within the region of interaction with FANCD2 (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G305R, G305D, A309P, T311P) have been reported in the Human Gene Mutation Database in association with MEN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, the S308P variant is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2021 | The p.S308P variant (also known as c.922T>C), located in coding exon 6 of the MEN1 gene, results from a T to C substitution at nucleotide position 922. The serine at codon 308 is replaced by proline, an amino acid with similar properties. This alteration has been detected in multiple individuals with a clinical diagnosis and family histories consistent with Multiple Endocrine Neoplasia Type 1 (MEN1) (Ambry internal data). Based on internal structural analysis, this variant results in a decrease in structural stability (Huang J et al. Nature, 2012 Feb;482:542-6). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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
DEOGEN2
Pathogenic
D;.;.;.;.;D;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;.;.;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D;T
Sift4G
Benign
T;T;D;D;D;D;D;D;D;.
Polyphen
0.99, 1.0
.;D;D;D;D;D;D;D;D;.
Vest4
MutPred
0.80
.;.;.;.;.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;
MVP
MPC
2.4
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