rs104894266

Variant names:

• chr11-64807557-G-A
• rs104894266
• NM_001370259.2:c.778C>T

Your query was ambiguous. Multiple possible variants found:

• 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.Gln260*) 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:5
• 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 rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.778C>T	p.Gln260*	stop_gained	Exon 4 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.778C>T	p.Gln260*	stop_gained	Exon 4 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Jul 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 15, 2023

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.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). -

not provided Pathogenic:1

Nov 21, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) -

MEN1-related disorder Pathogenic:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in multiple individuals with features consistent with multiple endocrine neoplasia type 1 (MEN1) (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
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;