chr11-64806255-CG-GA

Variant names:

• chr11-64806255-CG-GA
• NM_001370259.2:c.1025_1026delCGinsTC
• MEN1 p.Ala342Val

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP2

The NM_001370259.2(MEN1):​c.1025_1026delCGinsTC​(p.Ala342Val) variant causes a missense 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A342P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• 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: 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: Uncertain_significance. The variant received 5 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, 22 uncertain in NM_001370259.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64806257-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 527265.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 pituitary gigantism, multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, 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.1025_1026delCGinsTC	p.Ala342Val	missense	N/A	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1040_1041delCGinsTC	p.Ala347Val	missense	N/A	NP_001394079.1
	MEN1	NM_001370251.2		c.1025_1026delCGinsTC	p.Ala342Val	missense	N/A	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.1025_1026delCGinsTC	p.Ala342Val	missense	N/A	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1025_1026delCGinsTC	p.Ala342Val	missense	N/A	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1025_1026delCGinsTC	p.Ala342Val	missense	N/A	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-64573727;