NM_001370259.2(MEN1):c.1429G>C (p.Glu477Gln) AND Multiple endocrine neoplasia, type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 3, 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:: RCV000632101.9

Allele description [Variation Report for NM_001370259.2(MEN1):c.1429G>C (p.Glu477Gln)]

NM_001370259.2(MEN1):c.1429G>C (p.Glu477Gln)

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.1429G>C (p.Glu477Gln)

HGVS:

NC_000011.10:g.64804738C>G
NG_008929.1:g.11557G>C
NG_033040.1:g.3504G>C
NM_000244.4:c.1444G>C
NM_001370251.2:c.1555G>C
NM_001370259.2:c.1429G>CMANE SELECT
NM_001370260.2:c.1429G>C
NM_001370261.2:c.1429G>C
NM_001370262.2:c.1324G>C
NM_001370263.2:c.1324G>C
NM_130799.3:c.1429G>C
NM_130800.3:c.1444G>C
NM_130801.3:c.1444G>C
NM_130802.3:c.1444G>C
NM_130803.3:c.1444G>C
NM_130804.3:c.1444G>C
NP_000235.3:p.Glu482Gln
NP_001357180.2:p.Glu519Gln
NP_001357188.2:p.Glu477Gln
NP_001357189.2:p.Glu477Gln
NP_001357190.2:p.Glu477Gln
NP_001357191.2:p.Glu442Gln
NP_001357192.2:p.Glu442Gln
NP_570711.1:p.Glu477Gln
NP_570711.2:p.Glu477Gln
NP_570712.2:p.Glu482Gln
NP_570713.2:p.Glu482Gln
NP_570714.2:p.Glu482Gln
NP_570715.2:p.Glu482Gln
NP_570716.2:p.Glu482Gln
LRG_509t2:c.1429G>C
LRG_509:g.11557G>C
LRG_509p2:p.Glu477Gln
NC_000011.9:g.64572210C>G
NM_130799.2:c.1429G>C

Protein change:

E442Q

Links:

dbSNP: rs863224526

NCBI 1000 Genomes Browser:

rs863224526

Molecular consequence:

NM_000244.4:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.1555G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.1429G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.1429G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.1429G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.1324G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.1324G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.1429G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.1444G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000753205	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 14, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820659	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	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

SCV000753205

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 14, 2017)

germline

clinical testing

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

SCV004820659

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 2023)

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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000753205.4

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MEN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 477 of the MEN1 protein (p.Glu477Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine.

#	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 All of Us Research Program, National Institutes of Health, SCV004820659.1

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

Description

This missense variant replaces glutamic acid with glutamine at codon 477 of the MEN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MEN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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