NM_001370259.2(MEN1):c.1382_1404dup (p.Glu469fs) AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 11, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000476906.8

Allele description [Variation Report for NM_001370259.2(MEN1):c.1382_1404dup (p.Glu469fs)]

NM_001370259.2(MEN1):c.1382_1404dup (p.Glu469fs)

Gene:

MEN1:menin 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_001370259.2(MEN1):c.1382_1404dup (p.Glu469fs)

HGVS:

NC_000011.10:g.64804769_64804791dup
NG_008929.1:g.11510_11532dup
NG_033040.1:g.3457_3479dup
NM_000244.4:c.1397_1419dup
NM_001370251.2:c.1508_1530dup
NM_001370259.2:c.1382_1404dupMANE SELECT
NM_001370260.2:c.1382_1404dup
NM_001370261.2:c.1382_1404dup
NM_001370262.2:c.1277_1299dup
NM_001370263.2:c.1277_1299dup
NM_130799.3:c.1382_1404dup
NM_130800.3:c.1397_1419dup
NM_130801.3:c.1397_1419dup
NM_130802.3:c.1397_1419dup
NM_130803.3:c.1397_1419dup
NM_130804.3:c.1397_1419dup
NP_000235.3:p.Glu474fs
NP_001357180.2:p.Glu511fs
NP_001357188.2:p.Glu469fs
NP_001357189.2:p.Glu469fs
NP_001357190.2:p.Glu469fs
NP_001357191.2:p.Glu434fs
NP_001357192.2:p.Glu434fs
NP_570711.1:p.Glu469fs
NP_570711.2:p.Glu469fs
NP_570712.2:p.Glu474fs
NP_570713.2:p.Glu474fs
NP_570714.2:p.Glu474fs
NP_570715.2:p.Glu474fs
NP_570716.2:p.Glu474fs
LRG_509t2:c.1382_1404dup
LRG_509:g.11510_11532dup
LRG_509p2:p.Glu469fs
NC_000011.9:g.64572234_64572235insCTCGGCCTCGGCCGCCTCGGCCT
NC_000011.9:g.64572241_64572263dup
NM_130799.2:c.1382_1404dup

Protein change:

E434fs

Links:

dbSNP: rs1555163780

NCBI 1000 Genomes Browser:

rs1555163780

Molecular consequence:

NM_000244.4:c.1397_1419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370251.2:c.1508_1530dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370259.2:c.1382_1404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370260.2:c.1382_1404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370261.2:c.1382_1404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370262.2:c.1277_1299dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370263.2:c.1277_1299dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130799.3:c.1382_1404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130800.3:c.1397_1419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130801.3:c.1397_1419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130802.3:c.1397_1419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130803.3:c.1397_1419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_130804.3:c.1397_1419dup - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541234	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 11, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15331604, 16449969, 17879353, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541234

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 11, 2016)

germline

clinical testing

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

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

Direct binding of DNA by tumor suppressor menin.

La P, Silva AC, Hou Z, Wang H, Schnepp RW, Yan N, Shi Y, Hua X.

J Biol Chem. 2004 Nov 19;279(47):49045-54. Epub 2004 Aug 24.

PubMed [citation]

PMID:: 15331604
PMCID:: PMC2858586

Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression.

La P, Desmond A, Hou Z, Silva AC, Schnepp RW, Hua X.

Oncogene. 2006 Jun 15;25(25):3537-46. Epub 2006 Jan 30.

PubMed [citation]

PMID:: 16449969

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000541234.5

#	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 inserts 23 nucleotides in exon 10 of the MEN1 mRNA (c.1382_1404dup), causing a frameshift at codon 469. This creates a premature translational stop signal in the last exon of the MEN1 mRNA (p.Glu469Argfs*98). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MEN1 protein, eliminating 142 C-terminal amino acid residues. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MEN1-related disease. This frameshift truncates the functionally conserved nuclear localization signal of the MEN1 protein. Experimental studies have shown that disruption of this region abrogates the ability of MEN1 to bind DNA, regulate target gene expression, and inhibit cell proliferation (PMID: 15331604, 16449969). In addition, a different frameshift variant (p.Arg516Glyfs*43) with a premature termination codon downstream of this frameshift has been reported to be a common cause of multiple endocrine neoplasia type 1 (PMID: 17879353) In summary, this is a novel variant that truncates an important functional domain in MEN1. For this reason, it 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

Last Updated: Sep 29, 2024

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