rs794728657

chr11-64809749-CCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001370259.2(MEN1):c.358_360del(p.Lys120del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,892 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. K120K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEN1 NM_001370259.2 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.17

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001370259.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-64809749-CCTT-C is Pathogenic according to our data. Variant chr11-64809749-CCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 201019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809749-CCTT-C is described in Lovd as [Pathogenic]. Variant chr11-64809749-CCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.358_360del	p.Lys120del	inframe_deletion	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.358_360del	p.Lys120del	inframe_deletion	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This variant, c.358_360del, results in the deletion of 1 amino acid(s) of the MEN1 protein (p.Lys120del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hyperparathyroidism and multiple endocrine neoplasia type 1 (PMID: 9103196, 12807514, 17879353, 22470073). It has also been observed to segregate with disease in related individuals. This variant is also known as K119del. ClinVar contains an entry for this variant (Variation ID: 201019). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MEN1 function (PMID: 15254225, 21819486). 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 04, 2019	The MEN1 c.358_360delAAG; p.Lys120del variant (rs794728657), also known as K119del, is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 (Chandrasekharappa 1997, Klein 2005, Lemos 2008, Tso 2003). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 201019), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single lysine residue leaving the rest of the protein in-frame, but functional analyses of the variant protein show destabilization of the MEN1 protein leading to degradation by the proteasome (Shimazu 2011, Yaguchi 2004). Based on available information, this variant is considered to be pathogenic. References: Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 276(5311):404-7. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 7(2):131-8. Lemos MC and Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008 Jan;29(1):22-32. Shimazu S et al. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011 102(11):2097-102. Tso AW et al. Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese. Clin Endocrinol (Oxf). 2003 Jul;59(1):129-35. Yaguchi H et al. Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway. Mol Cell Biol. 2004 Aug;24(15):6569-80. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 04, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2022

In-frame deletion of 1 amino acids in a non-repeat region; Published functional studies demonstrate a damaging effect: decreased protein expression and proteasomal degradation (Yaguchi et al., 2004; Shimazu et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Published functional studies demonstrate decrease in protein level due to proteasomal degradation (Yaguchi et al.,2004).; This variant is associated with the following publications: (PMID: 10849016, 26767918, 29134609, 9103196, 9215689, 26756113, 10660339, 10598193, 9709922, 26905068, 9709985, 9747036, 9439676, 9652567, 24915123, 26126205, 25527055, 11435815, 8878463, 11741745, 12050235, 12049533, 12746426, 9463336, 17879353, 12112656, 11836268, 15670192, 15714081, 29497973, 30324798, 33144682, 12807514, 30787465, 15254225, 21819486) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.358_360delAAG pathogenic mutation (also known as p.K120del) is located in coding exon 1 of the MEN1 gene. This pathogenic mutation results from an in-frame deletion of 3 nucleotides at positions 358 to 360. This results in the deletion of a lysine residue at codon 120. In a review of the literature, this mutation represented 1.7% of reported MEN1 mutations (Lemos MC et al. Hum Mutat. 2008 Jan;29(1):22-32). This mutation has been identified in multiple, ethnically-diverse individuals with a clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1), and has been shown to segregate with disease in several MEN1 families (Agarwal et al. Hum Molec Genet. 1997;6(7):169; Chandrasekharappa et al. Science. 1997;276:40; Shimizu S et al. Jpn. J. Cancer Res. 1997 Nov;88:1029-32; Sakurai et al. J Hum Genet. 1998;43:999; Tso et al. Clin Endocrinol. 2003;59:129; Goroshi M et al. Fam. Cancer. 2016 10;15:617-24; Bhatti TR et al. J. Clin. Endocrinol. Metab. 2016 Mar;101:914-22). This alteration was also identified in an individual diagnosed with an insulinoma (Bhatti TR et al. J. Clin. Endocrinol. Metab. 2016 Mar;101:914-22). Furthermore, functional data has demonstrated that this mutation leads to reduced protein expression (approximately 20% compared to wild type) due to rapid degradation of the mutant protein by the cell (Shimazu et al. Cancer Sci. 2011;102:2097; Yaguchi H et al. Mol. Cell. Biol. 2004 Aug;24(15):6569-80). Of note, this alteration is also designated as p.K119del in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794728657; hg19: chr11-64577221;