11-64804812-C-T

Variant names:

• chr11-64804812-C-T
• rs775922507
• NM_001370259.2:c.1355G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PM1 PM2 PM5 PP2 PP3 BP6 BS2

The NM_001370259.2(MEN1):​c.1355G>A​(p.Arg452Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,444,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R452W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.48
• 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: 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 37 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 chr11-64804813-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216815.
• 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, 0.836
• BP6: Variant 11-64804812-C-T is Benign according to our data. Variant chr11-64804812-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 576399.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.1355G>A	p.Arg452Gln	missense	Exon 10 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1496G>A	p.Arg499Gln	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1481G>A	p.Arg494Gln	missense	Exon 11 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.1355G>A	p.Arg452Gln	missense	Exon 10 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1355G>A	p.Arg452Gln	missense	Exon 10 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1355G>A	p.Arg452Gln	missense	Exon 11 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000874 AC: 2 AN: 228868 AF XY: 0.00000789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444662 Hom.: 0 Cov.: 43 AF XY: 0.00000139 AC XY: 1 AN XY: 718810

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000448 AC: 2 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111064

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000840 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Multiple endocrine neoplasia, type 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.93
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.79		Gain of ubiquitination at K459 (P = 0.0457)
MVP		0.99
MPC		2.4
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.99
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775922507; hg19: chr11-64572284; COSMIC: COSV53644605; COSMIC: COSV53644605;