rs587776841

chr11-64809857-TAGAC-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.249_252del(p.Ile85SerfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L83L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.57

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 11-64809857-TAGAC-T is Pathogenic according to our data. Variant chr11-64809857-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 16693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809857-TAGAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.249_252del	p.Ile85SerfsTer33	frameshift_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.249_252del	p.Ile85SerfsTer33	frameshift_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458904 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725592

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 07, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	The p.Ile85fs variant in MEN1 has been reported in multiple individuals with mul tiple endocrine neoplasia type 1 and segregated with disease in affected relativ es (Lemmens 1997, Lemos 2008). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino ac id sequence beginning at codon 85 and leads to a premature termination codon 33 amino acids downstream. Heterozygous loss-of-function is an established disease mechanism in multiple endocrine neoplasia type 1. In summary, this variant meets our criteria to be classified as pathogenic for multiple endocrine neoplasia ty pe 1 in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Ile85Serfs*33) 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: 9103196, 9215690, 15635078, 17623761, 17879353, 24915123). ClinVar contains an entry for this variant (Variation ID: 16693). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 18, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2022	Variant summary: MEN1 c.249_252delGTCT (p.Ile85SerfsX33) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 240006 control chromosomes (gnomAD). c.249_252delGTCT has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (e.g. Bassett_1998, Geerdink_2003, Wautot_2002). The variant was found in about 4.5% of all Multiple Endocrine Neoplasia Type 1 patients/families (Lemos_2008). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 05, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2020	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 patient with expected phenotype for this gene, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	Frameshift 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); Present in up to 4.5% of families with MEN1 (Lemos 2008); Also known as 249del4, 357del4, and 359del4; This variant is associated with the following publications: (PMID: 24915123, 29395620, 28130400, 28597079, 29036195, 27572829, 17879353, 32937789, 10856877, 9103196, 26767918, 24599222, 23093699, 19461164, 22740705, 17623761, 9709921, 17853334, 15281352, 9888389, 10617276, 9215689, 9671267, 10720085, 28870973, 30324798, 28968916, 30795813, 30339208) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.249_252delGTCT pathogenic mutation, located in coding exon 1 of the MEN1 gene, results from a deletion of 4 nucleotides at nucleotide positions 249 to 252, causing a translational frameshift with a predicted alternate stop codon (p.I85Sfs*33). This alteration has been detected in multiple unrelated families in which the proband and/or family members exhibited the following MEN1-related characteristics: hyperparathyroidism, pituitary tumors, endocrine pancreatic tumors, carcinoid tumors, as well as a gastrinoma (Cardinal JW et al. J. Med. Genet. 2005 Jan;42(1):69-74). Another study found this alteration in a large kindred with familial isolated hyperparathyroidism and no other symptoms of MEN1 (Karges W et al. J. Endocrinol. 2000 Jul;166:1-9). This alteration has also been detected in an individual who presented at five years of age with hyperinsulinaemic hypoglycemia due to an insulinoma; he was subsequently monitored for other signs of MEN1 syndrome and, five years following his initial diagnosis, was found to have parathyroid adenoma (Padidela R et al. Eur. J. Endocrinol. 2014 May;170:741-7). In a review of the over 1300 mutations identified in the MEN1 gene since its discovery in 1997, this frameshift mutation was found to be in 4.5% of unrelated MEN1 families (Lemos MC and Thakker RV. Human Mutation. 2008 Jan;29(1):22-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Lipoma, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 04, 1998

- -

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: rs587776841; hg19: chr11-64577329;