rs1114167536

Variant names:

• chr11-64804753-C-CCCACGGCT
• rs1114167536
• NM_001370259.2:c.1406_1413dupAGCCGTGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1406_1413dupAGCCGTGG​(p.Gly472SerfsTer90) 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: 1.07

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

Our verdict: Pathogenic. The variant received 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 91 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804753-C-CCCACGGCT is Pathogenic according to our data. Variant chr11-64804753-C-CCCACGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 428080.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.1406_1413dupAGCCGTGG	p.Gly472SerfsTer90	frameshift_variant	Exon 10 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1406_1413dupAGCCGTGG	p.Gly472SerfsTer90	frameshift_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3

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

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly472Serfs*90) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with a personal or family history of multiple endocrine neoplasia, type 1 (PMID: 15714081, 19491073). ClinVar contains an entry for this variant (Variation ID: 428080). This variant disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation (PMID: 15331604, 16449969). While functional studies have not been performed to directly test the effect of this variant on MEN1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1406_1413dupAGCCGTGG pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a duplication of 8 nucleotides at nucleotide position 1406, causing a translational frameshift with a predicted alternate stop codon (p.G472Sfs*90). This mutation has been reported in a female proband with hyperparathyroidism, bilateral parathyroid carcinomas and adenomas, pituitary macroadenoma, and gastrinomas (Shih RY et al. Endocr Pract. 2009 Sep-Oct;15(6):567-72). Another study found this mutation in 1/288 probands having at least two features of multiple endocrine neoplasia type 1 (MEN1) or at least one feature of MEN1 and a family history of at least one affected relative (Klein RD et al. Genet. Med. 2005 Feb;7:131-8). In addition to the clinical data presented in the literature, 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

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1114167536; hg19: chr11-64572225;