rs794728647

Variant names:

• chr11-64809788-G-A
• rs794728647
• NM_001370259.2:c.322C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64809788-G-A
• chr11-64809788-G-C
• chr11-64809788-G-T

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.322C>T​(p.Arg108*) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.66

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 11-64809788-G-A is Pathogenic according to our data. Variant chr11-64809788-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809788-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.322C>T	p.Arg108*	stop_gained	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.322C>T	p.Arg108*	stop_gained	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Jul 26, 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.Arg108*) 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: 9215690, 17853334, 22470073). ClinVar contains an entry for this variant (Variation ID: 201006). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 14713256, 10374130, 9683585, 9215690, 25527055, 12112656, 11524904, 11034102, 10980535, 18045958, 20660572, 12746426, 9920064, 9241276) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 28, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R108* pathogenic mutation (also known as c.322C>T), located in coding exon 1 of the MEN1 gene, results from a C to T substitution at nucleotide position 322. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been detected in numerous families with multiple endocrine neoplasia type 1 (MEN1) (Lemmens I et al. Hum Mol Genet. 1997;6(7):1177-83, Giraud S et al. Am. J. Hum. Genet., 1998 Aug;63:455-67; Jakobovitz-Picard O et al. Hum. Mutat., 2000 Sep;16:269; Wautot V et al. Hum. Mutat., 2002 Jul;20:35-47; Cardinal JW et al. J Med Genet. 2005;42(1);69-74, Jiang XH et al. Endocr Relat Cancer. 2007;14(4):1073-9). 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	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.89
GERP RS		5.0

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: rs794728647; hg19: chr11-64577260; COSMIC: COSV56341148; COSMIC: COSV56341148;