rs1555165485

Variant names:

• chr11-64807553-T-TGCTGCA
• rs1555165485
• NM_001370259.2:c.776_781dupTGCAGC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PP3 PP5_Moderate BP3

The NM_001370259.2(MEN1):​c.776_781dupTGCAGC​(p.Leu259_Gln260dup) variant causes a conservative inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 conservative_inframe_insertion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.67
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-64807553-T-TGCTGCA is Pathogenic according to our data. Variant chr11-64807553-T-TGCTGCA is described in ClinVar as Pathogenic. ClinVar VariationId is 527275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001370259.2

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.776_781dupTGCAGC	p.Leu259_Gln260dup	conservative_inframe_insertion splice_region	Exon 4 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.791_796dupTGCAGC	p.Leu264_Gln265dup	conservative_inframe_insertion splice_region	Exon 4 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.776_781dupTGCAGC	p.Leu259_Gln260dup	conservative_inframe_insertion splice_region	Exon 4 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.776_781dupTGCAGC	p.Leu259_Gln260dup	conservative_inframe_insertion splice_region	Exon 4 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.776_781dupTGCAGC	p.Leu259_Gln260dup	conservative_inframe_insertion splice_region	Exon 4 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.776_781dupTGCAGC	p.Leu259_Gln260dup	conservative_inframe_insertion splice_region	Exon 5 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.776_781dup, results in the insertion of 2 amino acid(s) of the MEN1 protein (p.Leu259_Gln260dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 12417605; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 527275). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

Sep 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=16/84	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1555165485; hg19: chr11-64575025;