NM_001370259.2(MEN1):c.1307G>A (p.Trp436Ter) AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 11, 2019
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:: RCV000018167.10

Allele description [Variation Report for NM_001370259.2(MEN1):c.1307G>A (p.Trp436Ter)]

NM_001370259.2(MEN1):c.1307G>A (p.Trp436Ter)

Gene:

MEN1:menin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_001370259.2(MEN1):c.1307G>A (p.Trp436Ter)

HGVS:

NC_000011.10:g.64805077C>T
NG_008929.1:g.11218G>A
NG_033040.1:g.3165G>A
NM_000244.4:c.1322G>A
NM_001370251.2:c.1433G>A
NM_001370259.2:c.1307G>AMANE SELECT
NM_001370260.2:c.1307G>A
NM_001370261.2:c.1307G>A
NM_001370262.2:c.1202G>A
NM_001370263.2:c.1202G>A
NM_130799.3:c.1307G>A
NM_130800.3:c.1322G>A
NM_130801.3:c.1322G>A
NM_130802.3:c.1322G>A
NM_130803.3:c.1322G>A
NM_130804.3:c.1322G>A
NP_000235.3:p.Trp441Ter
NP_001357180.2:p.Trp478Ter
NP_001357188.2:p.Trp436Ter
NP_001357189.2:p.Trp436Ter
NP_001357190.2:p.Trp436Ter
NP_001357191.2:p.Trp401Ter
NP_001357192.2:p.Trp401Ter
NP_570711.1:p.Trp436Ter
NP_570711.2:p.Trp436Ter
NP_570712.2:p.Trp441Ter
NP_570713.2:p.Trp441Ter
NP_570714.2:p.Trp441Ter
NP_570715.2:p.Trp441Ter
NP_570716.2:p.Trp441Ter
LRG_509t2:c.1307G>A
LRG_509:g.11218G>A
LRG_509p2:p.Trp436Ter
NC_000011.9:g.64572549C>T
NM_130799.2:c.1307G>A

Protein change:

W401*; TRP436TER

Links:

OMIM: 613733.0011; dbSNP: rs104894260

NCBI 1000 Genomes Browser:

rs104894260

Molecular consequence:

NM_000244.4:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370251.2:c.1433G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370259.2:c.1307G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370260.2:c.1307G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370261.2:c.1307G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370262.2:c.1202G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001370263.2:c.1202G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130799.3:c.1307G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130800.3:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130801.3:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130802.3:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130803.3:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_130804.3:c.1322G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000038446	OMIM	no assertion criteria provided	Pathogenic (Apr 18, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001211956	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15331604, 16449969, 9103196, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000038446

OMIM

no assertion criteria provided

Pathogenic
(Apr 18, 1997)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001211956

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2019)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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 OMIM, SCV000038446.2

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

Description

In a proband with MEN1 (131100), Chandrasekharappa et al. (1997) identified a heterozygous nonsense mutation in the MEN1 gene, converting codon 436 from tryptophan to stop (W436X).

#	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 Invitae, SCV001211956.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region (p.Thr580Argfs*8) have been determined to be pathogenic (PMID: 15331604, 16449969, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9103196). ClinVar contains an entry for this variant (Variation ID: 16687). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MEN1 gene (p.Trp436*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 175 amino acids of the MEN1 protein.

#	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: Feb 20, 2024

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