rs1064793169

Variant names:

• chr11-64806359-A-G
• rs1064793169
• NM_001370259.2:c.922T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001370259.2(MEN1):​c.922T>C​(p.Ser308Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.11
• Publications: 0 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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 32 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 multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 11-64806359-A-G is Pathogenic according to our data. Variant chr11-64806359-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 418293.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.922T>C	p.Ser308Pro	missense	Exon 7 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.937T>C	p.Ser313Pro	missense	Exon 7 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.922T>C	p.Ser308Pro	missense	Exon 7 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.922T>C	p.Ser308Pro	missense	Exon 7 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.922T>C	p.Ser308Pro	missense	Exon 7 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.922T>C	p.Ser308Pro	missense	Exon 8 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.012	D
Sift4G	Benign	0.061	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.80		Loss of sheet (P = 0.0181)
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.92
gMVP		0.98
Mutation Taster		=1/99	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: rs1064793169; hg19: chr11-64573831;