NM_001370259.2(MEN1):c.307del (p.Leu103fs) AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000018159.17

Allele description [Variation Report for NM_001370259.2(MEN1):c.307del (p.Leu103fs)]

NM_001370259.2(MEN1):c.307del (p.Leu103fs)

Gene:

MEN1:menin 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_001370259.2(MEN1):c.307del (p.Leu103fs)

HGVS:

NC_000011.10:g.64809804del
NC_000011.9:g.64577275del
NG_008929.1:g.6492del
NM_000244.4:c.307del
NM_001370251.2:c.307del
NM_001370259.2:c.307delMANE SELECT
NM_001370260.2:c.307del
NM_001370261.2:c.307del
NM_001370262.2:c.307del
NM_001370263.2:c.307del
NM_130799.3:c.307del
NM_130800.3:c.307del
NM_130801.3:c.307del
NM_130802.3:c.307del
NM_130803.3:c.307del
NM_130804.3:c.307del
NP_000235.3:p.Leu103fs
NP_001357180.2:p.Leu103fs
NP_001357188.2:p.Leu103fs
NP_001357189.2:p.Leu103fs
NP_001357190.2:p.Leu103fs
NP_001357191.2:p.Leu103fs
NP_001357192.2:p.Leu103fs
NP_570711.1:p.Leu103fs
NP_570711.2:p.Leu103fs
NP_570712.2:p.Leu103fs
NP_570713.2:p.Leu103fs
NP_570714.2:p.Leu103fs
NP_570715.2:p.Leu103fs
NP_570716.2:p.Leu103fs
LRG_509t2:c.307del
LRG_509:g.6492del
LRG_509p2:p.Leu103fs
NC_000011.9:g.64577275del
NC_000011.9:g.64577275delG
NC_000011.9:g.64577276del
NM_130799.2:c.307del
NM_130799.2:c.307delC
NM_130804.2:c.307delC
p.L103CfsX16
p.Leu103CysfsX16

Protein change:

L103fs

Links:

OMIM: 613733.0003; dbSNP: rs794728639

NCBI 1000 Genomes Browser:

rs794728639

Molecular consequence:

NM_000244.4:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370251.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370259.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370260.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370261.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370262.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370263.2:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130799.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130800.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130801.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130802.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130803.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130804.3:c.307del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 1 (MEN1)
Synonyms:: MEA I; MEN I; Endocrine adenomatosis multiple; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007540; MeSH: D018761; MedGen: C0025267; Orphanet: 652; OMIM: 131100

Recent activity

Clear Turn Off Turn On

aquaporin-7 isoform 5 [Homo sapiens]
aquaporin-7 isoform 5 [Homo sapiens]
gi|1774221272|ref|NP_001363121.1|

Protein
HS_3221_A1_B09_T7 CIT Approved Human Genomic Sperm Library D Homo sapiens genomi...
HS_3221_A1_B09_T7 CIT Approved Human Genomic Sperm Library D Homo sapiens genomic clone Plate=3221 Col=17 Row=C, genomic survey sequence
gi|3582798|gnl|dbGSS|284416|gb|AQ19 1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038438	OMIM	no assertion criteria provided	Pathogenic (Apr 18, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000628077	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12112656, 9103196, 15522929, 17853334, 28492532
SCV000711426	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 24, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15522929, 9103196, 24033266
SCV002500524	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 19, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9671267, 9215689, 9103196, 10090472, 9709921, 12112656, 15522929, 17853334 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000038438.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In probands from 2 families with MEN1 (131100) not known to be related, Chandrasekharappa et al. (1997) identified a heterozygous 1-bp deletion of nucleotide 416, a cytidine, in the MEN1 gene.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000628077.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711426.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500524.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine