NM_001370259.2(MEN1):c.774G>C (p.Gln258His) AND Multiple endocrine neoplasia, type 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 1, 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:: RCV000463800.20

Allele description [Variation Report for NM_001370259.2(MEN1):c.774G>C (p.Gln258His)]

NM_001370259.2(MEN1):c.774G>C (p.Gln258His)

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.774G>C (p.Gln258His)

HGVS:

NC_000011.10:g.64807561C>G
NG_008929.1:g.8734G>C
NG_033040.1:g.681G>C
NM_000244.4:c.789G>C
NM_001370251.2:c.774G>C
NM_001370259.2:c.774G>CMANE SELECT
NM_001370260.2:c.774G>C
NM_001370261.2:c.774G>C
NM_001370262.2:c.669G>C
NM_001370263.2:c.669G>C
NM_130799.3:c.774G>C
NM_130800.3:c.789G>C
NM_130801.3:c.789G>C
NM_130802.3:c.789G>C
NM_130803.3:c.789G>C
NM_130804.3:c.789G>C
NP_000235.3:p.Gln263His
NP_001357180.2:p.Gln258His
NP_001357188.2:p.Gln258His
NP_001357189.2:p.Gln258His
NP_001357190.2:p.Gln258His
NP_001357191.2:p.Gln223His
NP_001357192.2:p.Gln223His
NP_570711.1:p.Gln258His
NP_570711.2:p.Gln258His
NP_570712.2:p.Gln263His
NP_570713.2:p.Gln263His
NP_570714.2:p.Gln263His
NP_570715.2:p.Gln263His
NP_570716.2:p.Gln263His
LRG_509t2:c.774G>C
LRG_509:g.8734G>C
LRG_509p2:p.Gln258His
NC_000011.9:g.64575033C>G
NM_130799.2:c.774G>C

Protein change:

Q223H

Links:

dbSNP: rs374659656

NCBI 1000 Genomes Browser:

rs374659656

Molecular consequence:

NM_000244.4:c.789G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370251.2:c.774G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370259.2:c.774G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370260.2:c.774G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370261.2:c.774G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370262.2:c.669G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370263.2:c.669G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130799.3:c.774G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130800.3:c.789G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130801.3:c.789G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130802.3:c.789G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130803.3:c.789G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130804.3:c.789G>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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maturase K, partial (chloroplast) [Acer pseudoplatanus]
maturase K, partial (chloroplast) [Acer pseudoplatanus]
gi|1002153459|gb|AMM73386.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000373099	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000541212	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004194427	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 18, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004836535	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	16	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 Illumina Laboratory Services, Illumina, SCV000373099.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000541212.9

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

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 258 of the MEN1 protein (p.Gln258His). This variant is present in population databases (rs374659656, gnomAD 0.04%). 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: 41855). 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%. 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 Baylor Genetics, SCV004194427.2

#	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

From All of Us Research Program, National Institutes of Health, SCV004836535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces glutamine with histidine at codon 258 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 hereditary cancer in the literature. This variant has been identified in 6/282604 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		16	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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