rs1114167524

Variant names:

• chr11-64805159-A-AGGAC
• rs1114167524
• NM_001370259.2:c.1224_1225insGTCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1224_1225insGTCC​(p.Cys409ValfsTer41) variant causes a frameshift 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.34

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 104 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805159-A-AGGAC is Pathogenic according to our data. Variant chr11-64805159-A-AGGAC is described in ClinVar as [Pathogenic]. Clinvar id is 428066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1224_1225insGTCC	p.Cys409ValfsTer41	frameshift_variant	Exon 9 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1224_1225insGTCC	p.Cys409ValfsTer41	frameshift_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Nov 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift change truncates the functionally conserved NLS2 domain of the MEN1 protein. Experimental studies have shown that disruption of this region abrogates the ability of MEN1 to bind DNA, regulate target gene expression, and inhibit cell proliferation (PMID: 15331604, 16449969). For these reasons, this variant has been classified as Pathogenic. Several different truncations located downstream of this variant (p.Arg516Profs*15, p.Arg516Glyfs*43,  p.Gln554*) have been determined to be pathogenic (PMID: 9215690,  11578300, 15635078, 17879353). This suggests that deletion of this region of the MEN1 protein is causative of disease. This sequence change results in a premature translational stop signal in the MEN1 gene (p.Cys409Valfs*41). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 202 amino acids of the MEN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MEN1-related disease. ClinVar contains an entry for this variant (Variation ID: 428066). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 13, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1224_1225insGTCC pathogenic mutation, located in coding exon 8 of the MEN1 gene, results from an insertion of 4 nucleotides at position 1224, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

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: rs1114167524; hg19: chr11-64572631;