rs767319284

Positions:

• chr11-64804620-CG-C
• chr11-64804620-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1546del​(p.Arg516GlyfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,455,516 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.09

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 16 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 26 pathogenic variants in the truncated region.
• PP5: Variant 11-64804620-CG-C is Pathogenic according to our data. Variant chr11-64804620-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 200999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804620-CG-C is described in Lovd as [Pathogenic]. Variant chr11-64804620-CG-C is described in Lovd as [Pathogenic]. Variant chr11-64804620-CG-C is described in Lovd as [Pathogenic]. Variant chr11-64804620-CG-C is described in Lovd as [Pathogenic]. Variant chr11-64804620-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1546del	p.Arg516GlyfsTer43	frameshift_variant	10/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1546del	p.Arg516GlyfsTer43	frameshift_variant	10/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455516 Hom.: 0 Cov.: 42 AF XY: 0.00000552 AC XY: 4 AN XY: 724044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Arg516Glyfs*43) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the MEN1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type 1, or related disorders (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 17879353, 23321498). This variant is also known as 1650delC and 1656delC. ClinVar contains an entry for this variant (Variation ID: 200999). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2022	Variant summary: MEN1 c.1546delC (p.Arg516GlyfsX43) 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 allele was found at a frequency of 2.5e-05 in 237028 control chromosomes (gnomAD). c.1546delC has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (e.g. Bassett_1998, Cavaco_2002, Cuny_2013). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2018	The MEN1 c.1540delC; p.Arg516fs variant (rs794728642), also known as 1650delC or 1656delC, is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 1 (Agarwal 1997, Cardinal 2005, Cuny 2013, Ellard 2005, Giraud 1998, Schaaf 2007, Wautot 2002). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 200999), and is found in the Finnish European population with an allele frequency of 0.027% (5/18,304 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 43 amino acid residues not usually present. This variant is predicted to disrupt a nuclear localization signal, and similar disruptions have been shown to abrogate the ability for MEN1 protein to bind DNA and inhibit cell proliferation (La 2004). Based on available information, the p.Arg516fs variant is considered to be pathogenic. References: Agarwal SK et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 1997 Jul;6(7):1169-75. Cardinal JW et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005 Jan;42(1):69-74. Cuny T et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. Eur J Endocrinol. 2013 Mar 15;168(4):533-41. Ellard S et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005 Feb;62(2):169-75. Giraud S et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455-67. La P et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem. 2004 Nov 19;279(47):49045-54. Schaaf L et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp Clin Endocrinol Diabetes. 2007 Sep;115(8):509-17. Wautot V et al. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002 Jul;20(1):35-47. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2022	This frameshift variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. In the published literature, the variant has been reported in affected individuals with multiple endocrine neoplasia type 1 in the published literature (PMIDs: 9215689 (1997), 12112656 (2002), 15670192 (2005), 17853334 (2007), 31482957 (2019), and 32909176 (2021)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2023	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23321498, 9215689, 23933118, 12112656, 11836268, 12050235, 15670192, 10439966, 21916912, 9683585, 12746426, 11966739, 9463336, 17065424, 17853334, 17879353, 11419921, 31482957, 9465067) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.1546delC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1546, causing a translational frameshift with a predicted alternate stop codon (p.R516Gfs*43). This mutation has reported in numerous individuals with personal and/or family history consistent with multiple endocrine neoplasia type 1 (Agarwal SK et al, Hum. Mol. Genet. 1997 Jul; 6(7):1169-75;Lemos MC et al, Hum. Mutat. 2008 Jan; 29(1):22-32; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Ventura M et al. Arch Endocrinol Metab, 2019 Sep;63:516-523). Of note, this alterations is also designated as c.1656delC and c.1561del (NM_130802.2) 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

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: rs767319284; hg19: chr11-64572092;