rs869025185

Variant names:

• chr11-64805730-ACTC-A
• rs869025185
• NM_001370259.2:c.1087_1089delGAG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1087_1089delGAG​(p.Glu363del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000541178: Experimental studies have shown that this variant affects MEN1 function (PMID:21819486)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E363E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.98
• Publications: 2 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000541178: Experimental studies have shown that this variant affects MEN1 function (PMID: 21819486).; SCV002769408: Analysis of protein activity has established that this variant causes a reduction in menin protein stability and expression (PMID: 21819486).; SCV000321883: Published functional studies demonstrate a damaging effect: decreased menin protein expression and stability (Shimazu 2011); SCV000579625: "In a study analyzing the stability levels of menin protein, this alteration was shown to have ~30% menin stability when compared to wild type (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102)."
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 18 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001370259.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-64805730-ACTC-A is Pathogenic according to our data. Variant chr11-64805730-ACTC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16685.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.1087_1089delGAG	p.Glu363del	conservative_inframe_deletion	Exon 8 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1228_1230delGAG	p.Glu410del	conservative_inframe_deletion	Exon 9 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1213_1215delGAG	p.Glu405del	conservative_inframe_deletion	Exon 9 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.1087_1089delGAG	p.Glu363del	conservative_inframe_deletion	Exon 8 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1087_1089delGAG	p.Glu363del	conservative_inframe_deletion	Exon 8 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1087_1089delGAG	p.Glu363del	conservative_inframe_deletion	Exon 9 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Multiple endocrine neoplasia, type 1 (5)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=9/91	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: rs869025185; hg19: chr11-64573202;