chr11-64808019-C-G

Variant names:

• chr11-64808019-C-G
• rs376872829
• NM_001370259.2:c.526G>C

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.526G>C​(p.Ala176Pro) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000579682: "This mutation has also been the subject of numerous functional studies finding disruptions in the JunD and Wnt/β-catenin signaling pathways, abolishment of menin-RPA2 interaction, impaired homologous recombination-directed DNA repair, and selective targeting of this mutant protein for degradation in the proteosome (Agarwal S et al. Cell 1999 Jan; 96(1):143-52; Sukhodolets KE et al. Mol. Cell. Biol., 2003 Jan;23:493-509; Chen G et al. Mol. Cancer Res. 2008 Dec; 6(12):1894-907; Canaff L et al. J. Clin. Endocrinol. Metab. 2012 Feb; 97(2); Fang M et al. Mol. Cell. Biol. 2013 Jul; 33(13):2635-47)."; SCV000234751: Functional studies demonstrate that A176P results in reduced protein expression compared to wild-type, and that the resulting protein product is unstable (Canaff et al., 2012).; SCV000628085: Experimental studies have shown that this missense change affects MEN1 function (PMID:9989505, 11221882, 12509449, 19074834, 22090276, 23648481).; SCV003923244: Multiple publications have reported experimental evidence that this variant disrupts the normal activity of the protein (examples: Agarwal_1999, Chen_2008, Canaff_2012, Fang_2013).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A176T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.01
• Publications: 9 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000579682: "This mutation has also been the subject of numerous functional studies finding disruptions in the JunD and Wnt/β-catenin signaling pathways, abolishment of menin-RPA2 interaction, impaired homologous recombination-directed DNA repair, and selective targeting of this mutant protein for degradation in the proteosome (Agarwal S et al. Cell 1999 Jan; 96(1):143-52; Sukhodolets KE et al. Mol. Cell. Biol., 2003 Jan;23:493-509; Chen G et al. Mol. Cancer Res. 2008 Dec; 6(12):1894-907; Canaff L et al. J. Clin. Endocrinol. Metab. 2012 Feb; 97(2); Fang M et al. Mol. Cell. Biol. 2013 Jul; 33(13):2635-47)."; SCV000234751: Functional studies demonstrate that A176P results in reduced protein expression compared to wild-type, and that the resulting protein product is unstable (Canaff et al., 2012).; SCV000628085: Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 11221882, 12509449, 19074834, 22090276, 23648481).; SCV003923244: Multiple publications have reported experimental evidence that this variant disrupts the normal activity of the protein (examples: Agarwal_1999, Chen_2008, Canaff_2012, Fang_2013).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 26 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.983
• PP5: Variant 11-64808019-C-G is Pathogenic according to our data. Variant chr11-64808019-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 200975.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.526G>C	p.Ala176Pro	missense	Exon 3 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.541G>C	p.Ala181Pro	missense	Exon 3 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.526G>C	p.Ala176Pro	missense	Exon 3 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.526G>C	p.Ala176Pro	missense	Exon 3 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.526G>C	p.Ala176Pro	missense	Exon 3 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.526G>C	p.Ala176Pro	missense	Exon 4 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Multiple endocrine neoplasia, type 1 (2)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.91		Gain of loop (P = 0.0013)
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.050	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs376872829; hg19: chr11-64575491;