NM_001370259.2(MEN1):c.1399G>A (p.Ala467Thr) AND Multiple endocrine neoplasia, type 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 19, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000476178.14

Allele description [Variation Report for NM_001370259.2(MEN1):c.1399G>A (p.Ala467Thr)]

NM_001370259.2(MEN1):c.1399G>A (p.Ala467Thr)

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.1399G>A (p.Ala467Thr)

HGVS:

NC_000011.10:g.64804768C>T
NG_008929.1:g.11527G>A
NG_033040.1:g.3474G>A
NM_000244.4:c.1414G>A
NM_001370251.2:c.1525G>A
NM_001370259.2:c.1399G>AMANE SELECT
NM_001370260.2:c.1399G>A
NM_001370261.2:c.1399G>A
NM_001370262.2:c.1294G>A
NM_001370263.2:c.1294G>A
NM_130799.3:c.1399G>A
NM_130800.3:c.1414G>A
NM_130801.3:c.1414G>A
NM_130802.3:c.1414G>A
NM_130803.3:c.1414G>A
NM_130804.3:c.1414G>A
NP_000235.3:p.Ala472Thr
NP_001357180.2:p.Ala509Thr
NP_001357188.2:p.Ala467Thr
NP_001357189.2:p.Ala467Thr
NP_001357190.2:p.Ala467Thr
NP_001357191.2:p.Ala432Thr
NP_001357192.2:p.Ala432Thr
NP_570711.1:p.Ala467Thr
NP_570711.2:p.Ala467Thr
NP_570712.2:p.Ala472Thr
NP_570713.2:p.Ala472Thr
NP_570714.2:p.Ala472Thr
NP_570715.2:p.Ala472Thr
NP_570716.2:p.Ala472Thr
LRG_509t2:c.1399G>A
LRG_509:g.11527G>A
LRG_509p2:p.Ala467Thr
NC_000011.9:g.64572240C>T
NM_130799.2:c.1399G>A

Protein change:

A432T

Links:

dbSNP: rs779589005

NCBI 1000 Genomes Browser:

rs779589005

Molecular consequence:

NM_000244.4:c.1414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.1525G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.1294G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.1294G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.1414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.1414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.1414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.1414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.1414G>A - 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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AGENCOURT_77835843 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8643347 5', mRNA sequence
gi|95018485|gnl|dbEST|39160694|gb|E 69.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541174	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Dec 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004824511	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005060799	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 19, 2024)	unknown	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

SCV000541174

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Benign
(Dec 16, 2023)

germline

clinical testing

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

SCV004824511

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 26, 2023)

germline

clinical testing

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

SCV005060799

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 19, 2024)

unknown

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	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, SCV000541174.8

#	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

From All of Us Research Program, National Institutes of Health, SCV004824511.1

#	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 alanine with threonine at codon 467 of the MEN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 5/255980 chromosomes 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

From Baylor Genetics, SCV005060799.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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