11-64804745-TTCCTCGCCCCACGGC-TTCCTCGCCCCACGGCTCCTCGCCCCACGGC

Variant names:

• chr11-64804745-T-TTCCTCGCCCCACGGC
• rs1033303123
• NM_001370259.2:c.1407_1421dupGCCGTGGGGCGAGGA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The ENST00000450708.7(MEN1):​c.1407_1421dupGCCGTGGGGCGAGGA​(p.Glu474_Ala475insProTrpGlyGluGlu) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 ENST00000450708.7 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000450708.7.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000450708.7. 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.1407_1421dupGCCGTGGGGCGAGGA	p.Glu474_Ala475insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 10 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1548_1562dupGCCGTGGGGCGAGGA	p.Glu521_Ala522insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1533_1547dupGCCGTGGGGCGAGGA	p.Glu516_Ala517insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 11 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.1407_1421dupGCCGTGGGGCGAGGA	p.Glu474_Ala475insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1407_1421dupGCCGTGGGGCGAGGA	p.Glu474_Ala475insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1407_1421dupGCCGTGGGGCGAGGA	p.Glu474_Ala475insProTrpGlyGluGlu	disruptive_inframe_insertion	Exon 11 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

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

Other links and lift over

dbSNP: rs1033303123; hg19: chr11-64572217;