11-64805132-C-T

Variant names:

• chr11-64805132-C-T
• rs104894264
• NM_001370259.2:c.1252G>A

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1252G>A​(p.Asp418Asn) 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D418H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.83
• Publications: 37 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 27 ACMG points.

• PS1: Transcript NM_001370259.2 (MEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr11-64805132-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 201015.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, 0.949
• PP5: Variant 11-64805132-C-T is Pathogenic according to our data. Variant chr11-64805132-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16703.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.1252G>A	p.Asp418Asn	missense_variant	Exon 9 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1252G>A	p.Asp418Asn	missense_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000427 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:6

Aug 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 418 of the MEN1 protein (p.Asp418Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 1 (MEN1) (PMID: 9463336, 10762295, 11303512, 11836268, 12050235, 12112656, 12652570, 17766710). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16703). 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: 15254225, 21819486). For these reasons, this variant has been classified as Pathogenic. -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 26, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp423Asn variant in MEN1 has been reported in least 4 individuals with ME N1 and segregated with disease in at least 8 relatives from 1 family (Turner 200 2, Vierimaa 2007, Crepin 2003). It was also absent from large population studies . In vitro functional studies provide some evidence that the p.Asp423Asn variant may impact protein function (Shimazu 2011, Yaguchi 2004). In summary, this vari ant meets criteria to be classified as pathogenic for MEN1 in an autosomal domin ant manner based upon segregation studies, absence from controls, and functional evidence studies. -

not provided Pathogenic:4

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21819486, 15254225) -

Oct 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.1252G>A; p.Asp418Asn variant (rs104894264) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 syndrome (Basset 1998, Goroshi 2016, Kytola 2001, Verges 2002). Functional analyses show the variant protein is unstable and is rapidly degraded by the ubiquitin-proteasome pathway (Shimazu 2011, Yaguchi 2004). This variant is reported in ClinVar (Variation ID: 16703), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartic acid at codon 418 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.891). Based on available information, this variant is considered to be pathogenic. References: Bassett JH et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 1998 Feb;62(2):232-44. PMID: 9463336. Goroshi M et al. Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India. Fam Cancer. 2016 Oct;15(4):617-24. PMID: 26905068. Kytola S et al. Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. J Med Genet. 2001 Mar;38(3):185-9. PMID: 11303512. Shimazu S et al. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011 Nov;102(11):2097-102. PMID: 21819486. Verges B et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab. 2002 Feb;87(2):457-65. PMID: 11836268. Yaguchi H et al. Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway. Mol Cell Biol. 2004 Aug;24(15):6569-80. PMID: 15254225. -

Feb 15, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 11, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D418N pathogenic mutation (also known as c.1252G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1252. The aspartic acid at codon 418 is replaced by asparagine, an amino acid with highly similar properties. This pathogenic mutation was previously reported in two unrelated probands diagnosed with MEN1, with a history of parathyroid tumors and a carcinoid tumor, and was absent in 55 unrelated normal controls (Bassett et al. Am. J. Hum. Genet. 1998;62:232-244). This mutation was also seen to co-segregate with disease in a family with tumors of the parathyroid gland, endocrine pancreas, and anterior pituitary (Giraud et al. Am. J. Hum. Genet.1998 Aug;63(2):455-67), as well as in a family with parathyroid carcinoma, adrenal lesions, and pancreatic neuroendocrine tumors (Cinque L et al. Endocr Connect. 2017 Nov;6(8):886-891). In another study, this mutation is noted to be involved in the JunD-binding domains and is predicted to prevent menin's repressive action on JunD-mediated transcription (Turner et al. J Clin Endocrinol Metab. 2002;87:2688-2693). Furthermore, other functional studies have demonstrated reduced stability and expression of the menin protein compared with wild-type (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102; Yaguchi Het al. Mol. Cell. Biol. 2004 Aug; 24(15):6569-80). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;M;M;M
PhyloP100		6.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.92
MutPred		0.81		.;.;.;.;Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.83
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104894264; hg19: chr11-64572604; COSMIC: COSV53641849;