11-64804708-A-G

Variant names:

• chr11-64804708-A-G
• rs1057427859
• NM_001370259.2:c.1459T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.1459T>C​(p.Ser487Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 5 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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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.

• 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 multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.

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.1459T>C	p.Ser487Pro	missense	Exon 10 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1600T>C	p.Ser534Pro	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1585T>C	p.Ser529Pro	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.1459T>C	p.Ser487Pro	missense	Exon 10 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1459T>C	p.Ser487Pro	missense	Exon 10 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1459T>C	p.Ser487Pro	missense	Exon 11 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple endocrine neoplasia, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.056	T
Polyphen		0.90	P
Vest4		0.29
MutPred		0.43		Loss of phosphorylation at S492 (P = 1e-04)
MVP		0.86
MPC		2.4
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.64
gMVP		0.77
Mutation Taster		=63/37	polymorphism

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: rs1057427859; hg19: chr11-64572180;