rs1555163821

chr11-64804770-T-TCGGCCG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001370259.2(MEN1):c.1396_1397insCGGCCG(p.Ala464_Ala465dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E466E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001370259.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1396_1397insCGGCCG	p.Ala464_Ala465dup	inframe_insertion	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1396_1397insCGGCCG	p.Ala464_Ala465dup	inframe_insertion	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2020

This variant, c.1391_1396dupCGGCCG, results in the insertion of 2 amino acids to the MEN1 protein (p.Ala464_Ala465dup), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. This variant has not been reported in the literature in individuals with MEN1-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555163821; hg19: chr11-64572242;