rs794728630

Variant names:

• chr11-64804618-T-A
• rs794728630
• NM_001370259.2:c.1549A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64804618-T-A
• chr11-64804618-T-C
• chr11-64804618-T-G

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.1549A>T​(p.Lys517*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.38

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 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804618-T-A is Pathogenic according to our data. Variant chr11-64804618-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 200986.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.1549A>T	p.Lys517*	stop_gained	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.1549A>T	p.Lys517*	stop_gained	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

Aug 12, 2021

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.Lys517*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the MEN1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Arg554*) have been determined to be pathogenic (PMID: 11578300, 17158764, 17853334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 200986). This premature translational stop signal has been observed in individual(s) with granular, cellular tumours of the pituitary gland (PMID: 31275768). This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K517* pathogenic mutation (also known as c.1549A>T), located in coding exon 9 of the MEN1 gene, results from an A to T substitution at nucleotide position 1549. This changes the amino acid from a lysine to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 15.4% of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected (Ambry internal data). This variant was reported in individual(s) with features consistent with multiple endocrine neoplasia, type 1 (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
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.0091
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.73
GERP RS		2.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728630; hg19: chr11-64572090;