11-64807667-A-G

Variant names:

• chr11-64807667-A-G
• rs886039415
• NM_001370259.2:c.668T>C

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.668T>C​(p.Leu223Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L223R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.08
• Publications: 3 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 25 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 chr11-64807667-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3634203.Status of the report is criteria_provided_single_submitter, 1 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, 0.987
• PP5: Variant 11-64807667-A-G is Pathogenic according to our data. Variant chr11-64807667-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.668T>C	p.Leu223Pro	missense	Exon 4 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.683T>C	p.Leu228Pro	missense	Exon 4 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.668T>C	p.Leu223Pro	missense	Exon 4 of 11	NP_001357180.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.668T>C	p.Leu223Pro	missense	Exon 4 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.668T>C	p.Leu223Pro	missense	Exon 4 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.668T>C	p.Leu223Pro	missense	Exon 5 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Jun 24, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34183184, 12112656, 10849016]. This variant is expected to disrupt protein structure [Myriad internal data].

Jan 04, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 223 of the MEN1 protein (p.Leu223Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 9683585, 10849016, 12112656; internal data). This variant is also known as c.683T>C (p.Leu228Pro). ClinVar contains an entry for this variant (Variation ID: 265236). 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%. For these reasons, this variant has been classified as Pathogenic.

Feb 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jul 02, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12112656, 9683585, 22470073, 12652570, 30869828, 28597079, 11836268, 10849016)

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 27, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L223P pathogenic mutation (also known as c.668T>C), located in coding exon 3 of the MEN1 gene, results from a T to C substitution at nucleotide position 668. The leucine at codon 223 is replaced by proline, an amino acid with similar properties. This alteration has been reported multiple unrelated individuals meeting clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1) (Giraud S et al. Am J Hum Genet. 1998 Aug;63(2):455-67; Roijers J et al. Eur J Clin Invest. 2000 Jun;30(6):487-92; Wautot V et al. Hum Mut. 2002;20(1):35-47; Ambry internal data). This pathogenic mutation has been shown to segregate with disease in our internal cohort (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.88		Gain of loop (P = 0.0045)
MVP		1.0
MPC		2.7
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.079	Neutral
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs886039415; hg19: chr11-64575139; COSMIC: COSV53648790; COSMIC: COSV53648790;