rs794728640

Variant names:

• chr11-64807913-ACTGT-A
• rs794728640
• NM_001370259.2:c.628_631delACAG

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.628_631delACAG​(p.Thr210SerfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.90

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64807913-ACTGT-A is Pathogenic according to our data. Variant chr11-64807913-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 200997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807913-ACTGT-A is described in Lovd as [Pathogenic]. Variant chr11-64807913-ACTGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.628_631delACAG	p.Thr210SerfsTer13	frameshift_variant	Exon 3 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.628_631delACAG	p.Thr210SerfsTer13	frameshift_variant	Exon 3 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Nov 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 22, 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.Thr210Serfs*13) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9709921, 10664520, 17879353, 22026581, 23154721, 25309785). ClinVar contains an entry for this variant (Variation ID: 200997). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Apr 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.643_646delACAG, c.735del4, or c.738delACAG; This variant is associated with the following publications: (PMID: 9709921, 15714081, 9683585, 10090472, 29036195, 30324798, 23154721, 9215689, 24599222, 20833329, 17879353, 23933118, 16563611, 15670192, 12112656, 9747036, 12746426, 12049533, 11966739, 12166655, 9103196, 15635078, 26767918, 28870973, 10664520) -

Sep 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.628_631delACAG, p.Thr210fs variant (rs794728640) has been reported in multiple families with multiple endocrine neoplasia type 1 (Cardinal 2005, Chandrasekharappa 1997, Jager 2006, Klein 2005, Ozveren 2012, Teh 1998). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, the variant is classified as pathogenic. References: Cardinal J et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005; 42(1):69-74. PMID: 15635078 Chandrasekharappa S et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997; 276(5311):404-7. PMID: 9103196. Jager A et al. Characteristics of the Danish families with multiple endocrine neoplasia type 1. Mol Cell Endocrinol. 2006; 249(1-2):123-32. PMID: 16563611. Klein R et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005; 7(2):131-8. PMID: 15714081. Ozveren A et al. A puzzling case of phospho-soda-induced hypocalcemia in a patient with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. Intern Med. 2012; 51(22):3145-9. PMID: 23154721. Teh B et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab. 1998; 83(8):2621-6. PMID: 9709921 -

Jul 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

his variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. This variant has been reported in numerous patients with Multiple Endocrine Neoplasia Type 1 in the published literature (PMID: 22026581 (2012), 25309785 (2014), 28870973 (2017), and 29036195 (2017)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628_631delACAG pathogenic mutation, located in coding exon 2 of the MEN1 gene, results from a deletion of 4 nucleotides at nucleotide positions 628 to 631, causing a translational frameshift with a predicted alternate stop codon (p.T210Sfs*13). This mutation has been previously reported in multiple individuals diagnosed with MEN1 (Chandrasekharappa SC et al. Science. 1997 Apr 18;276(5311):404-7; Jager AC et al. Mol. Cell. Endocrinol. 2006 Apr;249(1-2):123-32; Lemos MC and Thakker RV. Hum. Mutat. 2008 Jan;29(1):22-32; Belar O et al. Clin. Endocrinol. (Oxf) 2012 May;76(5):719-24; Ozveren A et al. Intern. Med. 2012;51(22):3145-9; Padidela R et al. Eur. J. Endocrinol. 2014 May; 170(5):741-7; Pardi E et al. PLoS ONE. 2017 Oct;12(10):e0186485). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728640; hg19: chr11-64575385;