rs1060499974

Positions:

• chr11-64805141-G-A

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.1243C>T​(p.Arg415*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.60

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]

MEN1 (HGNC:):

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 98 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805141-G-A is Pathogenic according to our data. Variant chr11-64805141-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 403802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805141-G-A is described in Lovd as [Pathogenic]. Variant chr11-64805141-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.1243C>T	p.Arg415*	stop_gained	9/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1243C>T	p.Arg415*	stop_gained	9/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Feb 15, 2022	ACMG categories: PVS1,PM2,PP3,PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 403802). This variant is also known as c.1258C>T, p.R420X. This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215690, 9329390, 11836268, 15670192, 17555499, 20833329, 25824098). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg415*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 01, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2024	Variant summary: MEN1 c.1243C>T (p.Arg415X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251116 control chromosomes. c.1243C>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 and segregated with disease in at least one family (e.g. Lemmens_1997, Marini_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9215690, 29497973). ClinVar contains an entry for this variant (Variation ID: 403802). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This variant changes 1 nucleotide in exon 9 of the MEN1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported as a recurrent mutation found in individuals and families affected with MEN1 (PMID: 9215690, 9329390, 10664520, 11836268, 12112656, 15670192, 17555499, 17853334, 22026581, 25309785, 25824098, 28298337, 28870973, 29036195, 29927501, 30324798, 34183184). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 19, 2014	The MEN1 c.1243C>T (p.Arg415*) nonsense variant (also known as c.1258C>T (p.Arg420*)) causes the premature termination of MEN1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families with MEN1 syndrome (PMIDs: 30324798 (2018), 24915123 (2014), 22577108 (2012), 15714081 (2005), 15670192 (2005), 9215690 (1997)), and shown to have deleterious effects on cell cycle arrest (PMID: 24997771 (2014)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2023	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25309785, 15670192, 34655802, 10870030, 9215690, 22577108, 24997771, 25525159, 19461164, 22026581, 26767918, 28693130, 17555499, 20833329, 29927501, 29625052, 10664520, 10812010, 12652570, 11836268, 36451132, 12112656, 29036195, 30324798, 28870973) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2021

The p.R415* pathogenic mutation (also known as c.1243C>T), located in coding exon 8 of the MEN1 gene, results from a C to T substitution at nucleotide position 1243. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration was among the first mutations to be identified in the MEN1 gene and has since been described in numerous individuals with classic findings of multiple endocrine neoplasia type 1 (MEN1) (Lemmens I et al. Hum. Mol. Genet. 1997 Jul;6(7):1177-83; Morelli A et al. Eur. J. Endocrinol. 2000 Feb;142(2):131-7; Klein RD et al. Genet. Med. 2005 Feb;7(2):131-8; Filopanti M et al. Eur. J. Endocrinol. 2012 Aug;167(2):157-64; Chung YJ et al. Endocrinol. Metab. (Seoul) 2014 Sep;29(3):270-9; Pardi E et al. PLoS One. 2017 Oct;12(10):e0186485). One review article estimated that the p.R415* mutation had been identified in 1.5% of reported MEN1 families (Lemos MC et al. Hum. Mutat. 2008 Jan;29(1):22-32). 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	0.62
CADD	Pathogenic	52
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.96
GERP RS		3.7

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: rs1060499974; hg19: chr11-64572613; COSMIC: COSV53641032; COSMIC: COSV53641032;