NM_001370259.2(MEN1):c.1400_1413del (p.Ala467fs) AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 8, 2023
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:: RCV000813744.11

Allele description [Variation Report for NM_001370259.2(MEN1):c.1400_1413del (p.Ala467fs)]

NM_001370259.2(MEN1):c.1400_1413del (p.Ala467fs)

Gene:

MEN1:menin 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_001370259.2(MEN1):c.1400_1413del (p.Ala467fs)

HGVS:

NC_000011.10:g.64804756_64804769del
NG_008929.1:g.11528_11541del
NG_033040.1:g.3475_3488del
NM_000244.4:c.1415_1428del
NM_001370251.2:c.1526_1539del
NM_001370259.2:c.1400_1413delMANE SELECT
NM_001370260.2:c.1400_1413del
NM_001370261.2:c.1400_1413del
NM_001370262.2:c.1295_1308del
NM_001370263.2:c.1295_1308del
NM_130799.3:c.1400_1413del
NM_130800.3:c.1415_1428del
NM_130801.3:c.1415_1428del
NM_130802.3:c.1415_1428del
NM_130803.3:c.1415_1428del
NM_130804.3:c.1415_1428del
NP_000235.3:p.Ala472fs
NP_001357180.2:p.Ala509fs
NP_001357188.2:p.Ala467fs
NP_001357189.2:p.Ala467fs
NP_001357190.2:p.Ala467fs
NP_001357191.2:p.Ala432fs
NP_001357192.2:p.Ala432fs
NP_570711.1:p.Ala467fs
NP_570711.2:p.Ala467fs
NP_570712.2:p.Ala472fs
NP_570713.2:p.Ala472fs
NP_570714.2:p.Ala472fs
NP_570715.2:p.Ala472fs
NP_570716.2:p.Ala472fs
LRG_509t2:c.1400_1413del
LRG_509:g.11528_11541del
LRG_509p2:p.Ala467fs
NC_000011.9:g.64572226_64572239del
NC_000011.9:g.64572228_64572241del
NM_130799.2:c.1400_1413del
NM_130799.2:c.1400_1413del14
NM_130799.2:c.1400_1413delCCGAGGAGCCGTGG

Protein change:

A432fs

Links:

dbSNP: rs1592633463

NCBI 1000 Genomes Browser:

rs1592633463

Molecular consequence:

NM_000244.4:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370251.2:c.1526_1539del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370259.2:c.1400_1413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370260.2:c.1400_1413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370261.2:c.1400_1413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370262.2:c.1295_1308del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370263.2:c.1295_1308del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130799.3:c.1400_1413del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130800.3:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130801.3:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130802.3:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130803.3:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130804.3:c.1415_1428del - frameshift variant - [Sequence Ontology: SO:0001589]

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

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PREDICTED: exosome complex component RRP4 homolog [Cucumis melo]
PREDICTED: exosome complex component RRP4 homolog [Cucumis melo]
gi|659128828|ref|XP_008464390.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000954115	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11578300, 17158764, 17853334, 28492532
SCV002074537	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17853334, 15331604, 34183184 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000954115

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002074537

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Prospective controlled trial of a standardized meal stimulation test in the detection of pancreaticoduodenal endocrine tumours in patients with multiple endocrine neoplasia type 1.

Langer P, Wild A, Celik I, Kopp I, Bergenfelz A, Bartsch DK.

Br J Surg. 2001 Oct;88(10):1403-7.

PubMed [citation]

PMID:: 11578300

Natural course of small, asymptomatic neuroendocrine pancreatic tumours in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study.

Kann PH, Balakina E, Ivan D, Bartsch DK, Meyer S, Klose KJ, Behr T, Langer P.

Endocr Relat Cancer. 2006 Dec;13(4):1195-202.

PubMed [citation]

PMID:: 17158764

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000954115.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ala467Glyfs*59) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the MEN1 protein. 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 (MEN1) (PMID: 17853334). This variant is also known as 1509del14. ClinVar contains an entry for this variant (Variation ID: 657179). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Gln554*) have been determined to be pathogenic (PMID: 11578300, 17158764, 17853334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074537.1

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

Description

Variant summary: MEN1 c.1400_1413del14 (p.Ala467GlyfsX59) 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 and HGMD. This variant is also known as c.1385_1398del14, p.Ala462GlyfsX59 in HGVS and 1509del14 in the literature. The variant was absent in 226168 control chromosomes (gnomAD). c.1400_1413del14 has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia (examples: Schaaf_2007 and Shariq_2022). These data indicate that the variant is associated with disease. One experimental study has demonstrated a truncation at the amino acid residue 527 (one amino acid downstream of the current truncation) abrogates the ability of MEN1 to bind DNA and repress cell proliferation (La_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and 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

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