NM_001370259.2(MEN1):c.526G>A (p.Ala176Thr) AND Multiple endocrine neoplasia, type 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 14, 2024
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:: RCV001060544.9

Allele description [Variation Report for NM_001370259.2(MEN1):c.526G>A (p.Ala176Thr)]

NM_001370259.2(MEN1):c.526G>A (p.Ala176Thr)

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.526G>A (p.Ala176Thr)

HGVS:

NC_000011.10:g.64808019C>T
NG_008929.1:g.8276G>A
NG_033040.1:g.223G>A
NM_000244.4:c.541G>A
NM_001370251.2:c.526G>A
NM_001370259.2:c.526G>AMANE SELECT
NM_001370260.2:c.526G>A
NM_001370261.2:c.526G>A
NM_001370262.2:c.526G>A
NM_001370263.2:c.526G>A
NM_130799.3:c.526G>A
NM_130800.3:c.541G>A
NM_130801.3:c.541G>A
NM_130802.3:c.541G>A
NM_130803.3:c.541G>A
NM_130804.3:c.541G>A
NP_000235.3:p.Ala181Thr
NP_001357180.2:p.Ala176Thr
NP_001357188.2:p.Ala176Thr
NP_001357189.2:p.Ala176Thr
NP_001357190.2:p.Ala176Thr
NP_001357191.2:p.Ala176Thr
NP_001357192.2:p.Ala176Thr
NP_570711.1:p.Ala176Thr
NP_570711.2:p.Ala176Thr
NP_570712.2:p.Ala181Thr
NP_570713.2:p.Ala181Thr
NP_570714.2:p.Ala181Thr
NP_570715.2:p.Ala181Thr
NP_570716.2:p.Ala181Thr
LRG_509t2:c.526G>A
LRG_509:g.8276G>A
LRG_509p2:p.Ala176Thr
NC_000011.9:g.64575491C>T
NM_130799.2:c.526G>A

Protein change:

A176T

Links:

dbSNP: rs376872829

NCBI 1000 Genomes Browser:

rs376872829

Molecular consequence:

NM_000244.4:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.541G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001225240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 5, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9215689, 9989505, 11221882, 12509449, 22090276, 23648481, 28492532
SCV004836543	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9215689, 9989505, 11221882, 12509449, 22090276, 23648481, 25741868
SCV005060801	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 14, 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

SCV001225240

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 5, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004836543

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 15, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005060801

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 14, 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

Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.

Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ.

Hum Mol Genet. 1997 Jul;6(7):1169-75.

PubMed [citation]

PMID:: 9215689

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225240.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 176 of the MEN1 protein (p.Ala176Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 825603). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala176 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 9989505, 11221882, 12509449, 22090276, 23648481; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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, SCV004836543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces alanine with threonine at codon 176 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 nor has this variant been reported as a germline mutation in individuals affected with hereditary cancer in the literature. A different missense variant at this codon, p.Ala176Pro, is considered disease-causing in ClinVar (variation ID 200975) and has been detected in a family affected with MEN1 (PMID: 9215689) and functional studies have shown the p.Ala176Pro variant to be unstable and exhibited loss of function in the binding and regulation of JunD and in homology-directed repair and response to DNA damage (PMID: 9989505, 11221882, 12509449, 22090276, 23648481). This variant has been identified in 1/251222 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, SCV005060801.1

#	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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