rs1114167531

chr11-64804777-C-CCTCGGCCT

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.1389_1390insAGGCCGAG(p.Ala464ArgfsTer98) 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: 33)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.253

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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 100 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804777-C-CCTCGGCCT is Pathogenic according to our data. Variant chr11-64804777-C-CCTCGGCCT is described in ClinVar as [Pathogenic]. Clinvar id is 428075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1389_1390insAGGCCGAG	p.Ala464ArgfsTer98	frameshift_variant	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1389_1390insAGGCCGAG	p.Ala464ArgfsTer98	frameshift_variant	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2017

For these reasons, this variant has been classified as Pathogenic. This frameshift disrupts the functionally conserved nuclear localization signal 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). In addition, a different frameshift variant (p.Arg516Glyfs*43) with a premature termination codon downstream of this frameshift has been reported to be a common cause of multiple endocrine neoplasia type 1 (PMID: 17879353) This variant has been reported in an individual affected with multiple endocrine neoplasia type 1 (PMID: 12050235). ClinVar contains an entry for this variant (Variation ID: 428075). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MEN1 gene (p.Ala464Argfs*98). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acids of the MEN1 protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2017

The c.1382_1389dupAGGCCGAG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of AGGCCGAG at nucleotide position 1382, causing a translational frameshift with a predicted alternate stop codon (p.A464Rfs*98). This same 8 base pair duplication, referred to as "fs 96 aa X", was detected in 1 of 34 unrelated MEN1 probands (Turner JJ, J. Clin. Endocrinol. Metab. 2002 Jun; 87(6):2688-93). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1114167531; hg19: chr11-64572249;