NM_001370259.2(MEN1):c.1308G>T (p.Trp436Cys) AND Multiple endocrine neoplasia, type 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 28, 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:: RCV000318762.21

Allele description [Variation Report for NM_001370259.2(MEN1):c.1308G>T (p.Trp436Cys)]

NM_001370259.2(MEN1):c.1308G>T (p.Trp436Cys)

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.1308G>T (p.Trp436Cys)

HGVS:

NC_000011.10:g.64805076C>A
NG_008929.1:g.11219G>T
NG_033040.1:g.3166G>T
NM_000244.4:c.1323G>T
NM_001370251.2:c.1434G>T
NM_001370259.2:c.1308G>TMANE SELECT
NM_001370260.2:c.1308G>T
NM_001370261.2:c.1308G>T
NM_001370262.2:c.1203G>T
NM_001370263.2:c.1203G>T
NM_130799.3:c.1308G>T
NM_130800.3:c.1323G>T
NM_130801.3:c.1323G>T
NM_130802.3:c.1323G>T
NM_130803.3:c.1323G>T
NM_130804.3:c.1323G>T
NP_000235.3:p.Trp441Cys
NP_001357180.2:p.Trp478Cys
NP_001357188.2:p.Trp436Cys
NP_001357189.2:p.Trp436Cys
NP_001357190.2:p.Trp436Cys
NP_001357191.2:p.Trp401Cys
NP_001357192.2:p.Trp401Cys
NP_570711.1:p.Trp436Cys
NP_570711.1:p.Trp436Cys
NP_570711.2:p.Trp436Cys
NP_570712.2:p.Trp441Cys
NP_570713.2:p.Trp441Cys
NP_570714.2:p.Trp441Cys
NP_570715.2:p.Trp441Cys
NP_570716.2:p.Trp441Cys
LRG_509t2:c.1308G>T
LRG_509:g.11219G>T
LRG_509p2:p.Trp436Cys
NC_000011.9:g.64572548C>A
NM_130799.2:c.1308G>T

Protein change:

W401C

Links:

dbSNP: rs398124435

NCBI 1000 Genomes Browser:

rs398124435

Molecular consequence:

NM_000244.4:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.1434G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.1308G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.1308G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.1308G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.1203G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.1203G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.1308G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.1323G>T - missense variant - [Sequence Ontology: SO:0001583]

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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UI-R-DZ0-cko-n-09-0-UI.s1 NCI_CGAP_DZ0 Rattus norvegicus cDNA clone IMAGE:733853...
UI-R-DZ0-cko-n-09-0-UI.s1 NCI_CGAP_DZ0 Rattus norvegicus cDNA clone IMAGE:7338539 3', mRNA sequence
gi|18189132|gnl|dbEST|10816572|gb|B 79.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541191	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9103196, 21127195, 21819486, 22090276, 15714081, 28492532
SCV002022786	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541191

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 28, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002022786

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 6, 2019)

germline

clinical testing

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

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

Positional cloning of the gene for multiple endocrine neoplasia-type 1.

Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, et al.

Science. 1997 Apr 18;276(5311):404-7.

PubMed [citation]

PMID:: 9103196

The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization.

Wang Y, Ozawa A, Zaman S, Prasad NB, Chandrasekharappa SC, Agarwal SK, Marx SJ.

Cancer Res. 2011 Jan 15;71(2):371-82. doi: 10.1158/0008-5472.CAN-10-3221. Epub 2010 Dec 2.

PubMed [citation]

PMID:: 21127195
PMCID:: PMC3076053

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000541191.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp436 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9103196, 21127195, 21819486). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MEN1 function (PMID: 22090276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 96250). This missense change has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 15714081; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 436 of the MEN1 protein (p.Trp436Cys).

#	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 Revvity Omics, Revvity, SCV002022786.3

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

#	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: Oct 13, 2024

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