rs1114167480
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.1013T>C(p.Leu338Pro) 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. L338V) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 5.24
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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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, 0.937
PP5
?
Variant 11-64806268-A-G is Pathogenic according to our data. Variant chr11-64806268-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64806268-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1013T>C | p.Leu338Pro | missense_variant | 7/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.1013T>C | p.Leu338Pro | 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 | May 08, 2017 | The L338P variant in the MEN1 gene has previously been published in at least one individual with multiple endocrine neoplasia type 1 (Tham et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L338P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located within the region of interaction with FANCD2 (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, L338P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2016 | The p.L338P variant (also known as c.1013T>C) is located in coding exon 6 of the MEN1 gene. This alteration results from a T to C substitution at nucleotide position 1013. The leucine at codon 338 is replaced by proline, an amino acid with similar properties. In a study of 200 unrelated Swedish index cases, this variant was reported in three affected members of one family. The proband was diagnosed with primary hyperparathyroidism with hyperplasia, an endocrine enteropancreatic gastrinoma, and an anterior pituitary tumor. The family members were diagnosed with hyperparathyriodism and insulinoma (Tham et al. J of Clinical Endocrinology & Metab. 2007. 92(9):3389-3395). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 7000 alleles tested) in our clinical cohort. Based on protein sequence alignment, 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
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
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
T;D;D;D;D;D;D;D;D;.
Polyphen
1.0, 1.0
.;D;D;D;D;D;D;D;D;.
Vest4
MutPred
0.75
.;.;.;.;.;Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);.;
MVP
MPC
2.5
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