chr11-64806322-G-A

Variant names:

• chr11-64806322-G-A
• rs1114167469
• NM_001370259.2:c.959C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.959C>T​(p.Pro320Leu) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000579628: Functional studies suggest that the p.P320L mutation affects nm23/NDP kinase binding (Ohkura N et al. Biochem Biophys Res Commun. 2001 Apr 20;282(5):1206-10; Wautot V et al. Hum. Mutat. 2002 Jul;20:35-47) and causes low menin expression levels as a result of degradation via the ubiquitin- proteasome pathway (Yaguchi H et al. Mol Cell Biol. 2004 Aug;24(15):6569-80). This alteration has also exhibited reduced stability and expression when compared to wild type (Shimazu S et al. Cancer Sci., 2011 Nov;102:2097-102).; SCV002771296: Experiments show this variant results in reduced protein expression (PMID:15254225, 21819486).; SCV004294850: Experimental studies have shown that this missense change affects MEN1 function (PMID:11302744, 12145286, 21819486).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P320R) 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:3
• Conservation: PhyloP100: 8.77
• Publications: 7 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000579628: Functional studies suggest that the p.P320L mutation affects nm23/NDP kinase binding (Ohkura N et al. Biochem Biophys Res Commun. 2001 Apr 20;282(5):1206-10; Wautot V et al. Hum. Mutat. 2002 Jul;20:35-47) and causes low menin expression levels as a result of degradation via the ubiquitin- proteasome pathway (Yaguchi H et al. Mol Cell Biol. 2004 Aug;24(15):6569-80). This alteration has also exhibited reduced stability and expression when compared to wild type (Shimazu S et al. Cancer Sci., 2011 Nov;102:2097-102).; SCV002771296: Experiments show this variant results in reduced protein expression (PMID: 15254225, 21819486).; SCV004294850: Experimental studies have shown that this missense change affects MEN1 function (PMID: 11302744, 12145286, 21819486).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 33 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 chr11-64806322-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 988340.
• 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 pituitary gigantism, multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-64806322-G-A is Pathogenic according to our data. Variant chr11-64806322-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428002.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.959C>T	p.Pro320Leu	missense	Exon 7 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.974C>T	p.Pro325Leu	missense	Exon 7 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.959C>T	p.Pro320Leu	missense	Exon 7 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.959C>T	p.Pro320Leu	missense	Exon 7 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.959C>T	p.Pro320Leu	missense	Exon 7 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.959C>T	p.Pro320Leu	missense	Exon 8 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Multiple endocrine neoplasia, type 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.91		Gain of helix (P = 0.0143)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1114167469; hg19: chr11-64573794; COSMIC: COSV53649700;