chr11-64809695-G-C

Variant names:

• chr11-64809695-G-C
• rs104894263
• NM_001370259.2:c.415C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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. H139Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.94
• Publications: 14 publications found

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]

MEN1 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 30 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64809693-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1677022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, 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 VariationId is 16699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.415C>G	p.His139Asp	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.415C>G	p.His139Asp	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Dec 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 139 of the MEN1 protein (p.His139Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MEN1-related conditions (PMID: 9215689, 21917868). ClinVar contains an entry for this variant (Variation ID: 16699). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 12509449, 14508515, 15254225, 21264250, 21819486, 22090276, 22275377, 22327296). 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. -

not provided Pathogenic:1

Jan 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.415C>G (p.His139Asp) variant has been reported in the published literature in affected individuals with multiple endocrine neoplasia type 1 (PMIDs: 9215689 (1997), 11134142 (2000), 15254225 (2004), 21917868 (2011), and 30324798 (2018)). Multiple functional studies have reported that this variant is damaging to protein function (PMIDs: 9989505 (1999), 12509449 (2003), 14508515 (2003), 15254225 (2004), 21264250 (2011), 21819486 (2011), 22090276 (2012), 22275377 (2012), 22327296 (2012), and 23648481 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 27, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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;.;.;.;.;.
PhyloP100		8.9
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
PromoterAI		-0.012	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894263; hg19: chr11-64577167;