rs104894266

Positions:

• chr11-64807557-G-A
• chr11-64807557-G-C

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.778C>T​(p.Gln260Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.67

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 11-64807557-G-A is Pathogenic according to our data. Variant chr11-64807557-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807557-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.778C>T	p.Gln260Ter	stop_gained	4/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.778C>T	p.Gln260Ter	stop_gained	4/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2023	This sequence change creates a premature translational stop signal (p.Gln260*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16690). This premature translational stop signal has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (PMID: 9215689). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -

MEN1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The MEN1 c.793C>T variant is predicted to result in premature protein termination (p.Gln265*). This variant has been reported in individuals with multiple endocrine neoplasia type 1 (see for example: Figure 1. Agarwal et al. 1997. PubMed ID: 9215689). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/16690/). Nonsense variants in MEN1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2020

The p.Q260* pathogenic mutation (also known as c.778C>T), located in coding exon 3 of the MEN1 gene, results from a C to T substitution at nucleotide position 778. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been identified in multiple individuals with clinical features consistent with MEN1 syndrome (Agarwal SK et al. Hum Mol Genet, 1997 Jul;6:1169-75; Shimizu S et al. Jpn J Cancer Res, 1997 Nov;88:1029-32; Pack S et al. J Invest Dermatol, 1998 Apr;110:438-40). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.87
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs104894266; hg19: chr11-64575029;