NM_001370259.2(MEN1):c.776T>C (p.Leu259Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 30, 2021
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:: RCV002414248.2

Allele description [Variation Report for NM_001370259.2(MEN1):c.776T>C (p.Leu259Pro)]

NM_001370259.2(MEN1):c.776T>C (p.Leu259Pro)

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.776T>C (p.Leu259Pro)

HGVS:

NC_000011.10:g.64807559A>G
NG_008929.1:g.8736T>C
NG_033040.1:g.683T>C
NM_000244.4:c.791T>C
NM_001370251.2:c.776T>C
NM_001370259.2:c.776T>CMANE SELECT
NM_001370260.2:c.776T>C
NM_001370261.2:c.776T>C
NM_001370262.2:c.671T>C
NM_001370263.2:c.671T>C
NM_130799.3:c.776T>C
NM_130800.3:c.791T>C
NM_130801.3:c.791T>C
NM_130802.3:c.791T>C
NM_130803.3:c.791T>C
NM_130804.3:c.791T>C
NP_000235.3:p.Leu264Pro
NP_001357180.2:p.Leu259Pro
NP_001357188.2:p.Leu259Pro
NP_001357189.2:p.Leu259Pro
NP_001357190.2:p.Leu259Pro
NP_001357191.2:p.Leu224Pro
NP_001357192.2:p.Leu224Pro
NP_570711.1:p.Leu259Pro
NP_570711.2:p.Leu259Pro
NP_570712.2:p.Leu264Pro
NP_570713.2:p.Leu264Pro
NP_570714.2:p.Leu264Pro
NP_570715.2:p.Leu264Pro
NP_570716.2:p.Leu264Pro
LRG_509t2:c.776T>C
LRG_509:g.8736T>C
LRG_509p2:p.Leu259Pro
NC_000011.9:g.64575031A>G
NM_130799.2:c.776T>C

Protein change:

L224P

Links:

dbSNP: rs2136139920

NCBI 1000 Genomes Browser:

rs2136139920

Molecular consequence:

NM_000244.4:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.671T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.671T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002672216	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18549467, 22327296 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002672216

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 30, 2021)

germline

clinical testing

PubMed (2)
[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

Novel germline mutations of the MEN1 gene in Greek families with multiple endocrine neoplasia type 1.

Peppa M, Boutati E, Kamakari S, Pikounis V, Peros G, Koutsodontis G, Metaxa-Mariatou V, Economopoulos T, Raptis SA, Hadjidakis D.

Clin Endocrinol (Oxf). 2009 Jan;70(1):75-81. doi: 10.1111/j.1365-2265.2008.03308.x. Epub 2008 Jun 12.

PubMed [citation]

PMID:: 18549467

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.

Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X, Lei M.

Nature. 2012 Feb 12;482(7386):542-6. doi: 10.1038/nature10806.

PubMed [citation]

PMID:: 22327296
PMCID:: PMC3983792

Details of each submission

From Ambry Genetics, SCV002672216.2

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

Description

The p.L259P variant (also known as c.776T>C), located in coding exon 3 of the MEN1 gene, results from a T to C substitution at nucleotide position 776. The leucine at codon 259 is replaced by proline, an amino acid with similar properties. This alteration has been identified in an individual diagnosed with primary hyperparathyroidism and non-functioning neuroendocrine tumors of the pancreas and stomach (Peppa M et al. Clin Endocrinol (Oxf), 2009 Jan;70:75-81). Based on internal structural analysis, this alteration causes significant destabilization of the Palm domain of MEN1 (Huang J et al. Nature, 2012 Feb;482:542-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be 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: May 1, 2024

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