11-64809695-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001370259.2(MEN1):​c.415C>G​(p.His139Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H139P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

MEN1
NM_001370259.2 missense

Scores

12
6
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.94
Variant links:
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 chrnull-null-null-null is described in UniProt as null.
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, 0.992
PP5
Variant 11-64809695-G-C is Pathogenic according to our data. Variant chr11-64809695-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809695-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MEN1NM_001370259.2 linkuse as main transcriptc.415C>G p.His139Asp missense_variant 2/10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkuse as main transcriptc.415C>G p.His139Asp missense_variant 2/105 NM_001370259.2 ENSP00000394933 P3O00255-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2000- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 08, 2021Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 12509449, 14508515, 15254225, 21264250, 21819486, 22090276, 22275377, 22327296). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 16699). This missense change has been observed in individuals with MEN1-related conditions (PMID: 9215689, 21917868). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with aspartic acid at codon 139 of the MEN1 protein (p.His139Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant disrupts the p.His139 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 30324798). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2018The p.H139D pathogenic mutation (also known as c.415C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 415. The histidine at codon 139 is replaced by aspartic acid, an amino acid with some similar properties. This alteration has been previously identified in numerous individuals with multiple endocrine neoplasia type 1 (MEN1) (Stratakis et al. J Clin Endocrinol Metab. 2000 Dec; 85(12): 4776-80; Farrell WE et al. J Clin Endocrinol Metab. 2011 Nov;96(11):E1905-14; Ambry Internal Data). Functional studies have shown that this alteration leads to decreased MEN1 protein stability and abnormal transcriptional regulation of downstream targets (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102; Agarwal SK et al. Hum Mol Genet.1997 Jul;6(7):1169-75; Canaff L et al. J Clin Endocrinol Metab. 2012 Feb;97(2):E282-91; Fang M et al. Mol. Cell. Biol., 2013 Jul;33:2635-47). Several other missense alterations at this codon (p.H139R, p.H139N, p.H139Q, p.H139P, p.H139Y) have also been identified in MEN1 probands (Martín-Campos JM et al. Diagn Mol Pathol. 1999 Dec;8(4):195-204; Cebrián A et al. J Med Genet. 2003 May;40(5):e72; Concolino P et al. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41; Pardi E et al. PLoS One. 2017 Oct 16;12(10):e0186485; Carvalho RA et al. Eur J Endocrinol. 2018 Dec 1;179(6):391-407). Of note, this alteration is also designated c.525C>G in the published literature. Based on the available evidence, p.H139D is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.92
D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.6
.;M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-8.2
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen
0.039, 1.0
.;B;D;D;D;D;D;D;D;.;.;.;.;.
Vest4
0.90
MutPred
0.95
Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);Gain of ubiquitination at K135 (P = 0.0436);
MVP
1.0
MPC
2.5
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.97
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894263; hg19: chr11-64577167; API