rs794728631

Positions:

• chr11-64804507-G-A
• chr11-64804507-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1660C>T​(p.Gln554Ter) variant causes a stop gained change involving the alteration of a 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: 32)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.28

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 14 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804507-G-A is Pathogenic according to our data. Variant chr11-64804507-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804507-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1660C>T	p.Gln554Ter	stop_gained	10/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1660C>T	p.Gln554Ter	stop_gained	10/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser555 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 200988). This variant is also known as c.1770C>T. This premature translational stop signal has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (MEN 1) (PMID: 11578300, 17158764, 17853334, 28321559). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln554*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the MEN1 protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2015

The Q554X nonsense mutation in the MEN1 gene has been reported previously in association with multiple endocrine neoplasia type 1 (Langer et al., 2001). This mutation is predicted to delete the last 57 amino acids of the protein, causing loss of normal protein function through protein truncation. The variant is found in MEN1 panel(s). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2019

The p.Q554* pathogenic mutation (also known as c.1660C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1660. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This pathogenic mutation has been reported in multiple individuals diagnosed with MEN1 (Langer P et al. Br. J. Surg. 2001 Oct;88(10):1403-7; Kann PH et al. Endocr. Relat. Cancer. 2006 Dec;13(4):1195-202; Schaaf L et al. Exp. Clin. Endocrinol. Diabetes 2007 Sep;115(8):509-17). 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
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.88
GERP RS		4.3

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: rs794728631; hg19: chr11-64571979;