Variant chr11-64805730-ACTC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_001370259.2(MEN1):c.1087_1089del(p.Glu363del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E363E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MEN1
NM_001370259.2 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.98

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_001370259.2

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001370259.2. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 11-64805730-ACTC-A is Pathogenic according to our data. Variant chr11-64805730-ACTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 16685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805730-ACTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1087_1089del	p.Glu363del	inframe_deletion	8/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1087_1089del	p.Glu363del	inframe_deletion	8/10	5	NM_001370259.2	P3	O00255-2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with multiple endocrine neoplasia 1 (MIM#131100), and familial isolated primary hyperparathyroidism (PMID: 31263451). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located at the MLL1 binding site within the annotated menin domain, forming a stable salt bride (NCBI, PMID: 22936661). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with multiple endocrine neoplasia type 1 (ClinVar, PMID: 9215689, PMID: 22026581). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Analysis of protein activity has established that this variant causes a reduction in menin protein stability and expression (PMID: 21819486). (SP) 1206 - This variant has been shown to be paternally inherited (19G001331). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 18, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2023	This variant, c.1087_1089del, results in the deletion of 1 amino acid(s) of the MEN1 protein (p.Glu363del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hyperparathyroidism and multiple endocrine neoplasia type 1 (PMID: 9215689, 11454510, 12050235, 22026581). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16685). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MEN1 function (PMID: 21819486). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect: decreased menin protein expression and stability (Shimazu 2011); Also known as c.1197_1199delGAG; This variant is associated with the following publications: (PMID: 12050235, 17711922, 9103196, 28193735, 9671267, 21819486, 10730900, 22026581, 11454510, 9354421, 9681840, 10617276, 15281352, 9215689, 29738674, 28881068, 11807402) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2024

The c.1087_1089delGAG pathogenic mutation (also known as p.E363del), located in coding exon 7 of the MEN1 gene, results from an in-frame GAG deletion between nucleotide positions 1087 and 1089. This results in the in-frame deletion of a glutamic acid residue at codon 363. This alteration has been detected in multiple individuals meeting the clinical criteria for a diagnosis of multiple endocrine neoplasia type 1 (Agarwal SK et al. Hum. Mol. Genet. 1997 Jul;6(7):1169-75; Belar O et al. Clin. Endocrinol. (Oxf). 2012 May;76:719-24; Ambry internal data). In another study, this alteration segregated with disease in five family members whose clinical symptoms included: primary hyperparathyroidism, mild hypercalcemia, and parathyroid hormone levels within the upper normal or slightly elevated range (Miedlich S et al. Eur. J. Endocrinol. 2001 Aug;145(2):155-60). In a study analyzing the stability levels of menin protein, this alteratioin was shown to have ~30% menin stability when compared to wild type (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing