rs386134247

Variant names:

• chr11-64805645-TC-T
• rs386134247
• NM_001370259.2:c.1174delG

Your query was ambiguous. Multiple possible variants found:

• chr11-64805645-TC-T
• chr11-64805645-TC-TCC

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.1174delG​(p.Glu392SerfsTer53) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E392E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.16
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805645-TC-T is Pathogenic according to our data. Variant chr11-64805645-TC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265238.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.1174delG	p.Glu392SerfsTer53	frameshift_variant	Exon 8 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1174delG	p.Glu392SerfsTer53	frameshift_variant	Exon 8 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Oct 24, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689). This variant is also known as 1280delG in the literature. ClinVar contains an entry for this variant (Variation ID: 265238). 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.Glu392Serfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acids of the MEN1 protein. This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region (p.Lys559Glufs*38) have been determined to be pathogenic (PMID: 10090472, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. -

Jan 23, 2018

Department of Laboratory Medicine, Soonchunhyang University Seoul Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 30, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1174delG variant has been reported previously (as 1280delG) in association with multiple endocrine neoplasia type 1 (Agarwal et al., 1997). The c.1174delG variant causes a frameshift starting with codon Glutamic acid 392, changes this amino acid to a Serine residue and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Glu392SerfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1174delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, c.1174delG is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1174delG pathogenic mutation, located in coding exon 7 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1174, causing a translational frameshift with a predicted alternate stop codon (p.E392Sfs*53). This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 35.8% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was reported in individual(s) with features consistent with MEN1 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs386134247; hg19: chr11-64573117;