rs794728639

Variant names:

• chr11-64809802-AG-A
• rs794728639
• NM_001370259.2:c.307delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.307delC​(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:9
• Conservation: PhyloP100: 2.83
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 200996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.307delC	p.Leu103CysfsTer16	frameshift_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.307delC	p.Leu103CysfsTer16	frameshift_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:5

Apr 18, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 11, 2025

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jul 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Mar 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Apr 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.307del; p.Leu103CysfsTer16 variant (rs794728639) is reported in the literature in multiple individuals affected with multiple endocrine neoplasia-type 1 (Benito 2005, Chandrasekharappa 1997, Klein 2005, Makri 2018, Mutch 1999, Schaaf 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 200996), and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Benito M et al. Gonadotroph tumor associated with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2005 Jan;90(1):570-4. PMID: 15522929 Chandrasekharappa SC et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7. PMID: 9103196 Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID: 15714081 Makri A et al. Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease. Clin Endocrinol (Oxf). 2018 Oct;89(4):437-443. PMID: 29927501 Mutch MG et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13(3):175-85. PMID: 10090472 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. PMID: 17853334 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 multiple endocrine neoplasia type 1 (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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
PhyloP100		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728639; hg19: chr11-64577274;