rs794728639

Positions:

• chr11-64809802-AG-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.307del​(p.Leu103CysfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L103L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.83

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 11-64809802-AG-A is Pathogenic according to our data. Variant chr11-64809802-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 200996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809802-AG-A is described in Lovd as [Pathogenic]. Variant chr11-64809802-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.307del	p.Leu103CysfsTer16	frameshift_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.307del	p.Leu103CysfsTer16	frameshift_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 18, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Leu103Cysfs*16) 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, 15522929, 17853334). This variant is also known as 416delC and 417delC. ClinVar contains an entry for this variant (Variation ID: 200996). 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	Mar 19, 2022	Variant summary: MEN1 c.307delC (p.Leu103CysfsX16) 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 250908 control chromosomes. c.307delC has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (example, Chandrasekharappa_1997, Mutch_1999, Benito_2005, Schaaf_2007). It has been reported with legacy names of 416delC, 417delC. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2017	The p.Leu103fs variant in MEN1 has been reported in 3 individuals with multiple endocrine neoplasia type 1 (MEN1; Chandrasekharappa 1997, Benito 2005) and has a lso been reported by other clinical laboratories in ClinVar (Variation ID 200996 ). It was absent from large population studies, though the ability of these stud ies to accurately detect indels may be limited. This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 103 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Hete rozygous loss of function of the MEN1 gene is an established disease mechanism i n MEN1 syndrome. In summary, this variant meets criteria to be classified as pat hogenic for MEN1 in an autosomal dominant manner based upon the predicted impact to the protein and absence from controls. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	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 (gnomAD); This variant is associated with the following publications: (PMID: 15281352, 15126560, 9103196, 9215689, 15522929, 10090472, 9709921, 9671267, 11579199, 9832038, 10617276, 9681840, 12112656, 17853334, 15082967, 17879353, 9437237, 17766710, 29927501, 31447099) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2021

The c.307delC pathogenic mutation, located in coding exon 1 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 307, causing a translational frameshift with a predicted alternate stop codon (p.L103Cfs*16). This mutation has been reported in multiple individuals/families with a clinical diagnosis of MEN1 syndrome (Chandrasekharappa SC et al. Science. 1997 Apr;276:404-7; Benito M et al. J. Clin. Endocrinol. Metab. 2005 Jan;90:570-4; Klein RD et al. Genet. Med. 2005 Feb;7:131-8; Mutch MG et al. Hum. Mutat. 1999;13:175-85; Makri A et al. Clin Endocrinol (Oxf), 2018 10;89:437-443; Tirosh A et al. Endocr Pract, 2019 Jun;25:580-588; Mandl A et al. Endocr Relat Cancer, 2021 Oct;28:L15-L19). Of note, this mutation is also designated as 416delC in published literature. 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs794728639; hg19: chr11-64577274;