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NM_000268.4(NF2):c.104T>G (p.Phe35Cys) AND Neurofibromatosis, type 2

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
May 24, 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:
RCV003608082.3

Allele description [Variation Report for NM_000268.4(NF2):c.104T>G (p.Phe35Cys)]

NM_000268.4(NF2):c.104T>G (p.Phe35Cys)

Gene:
NF2:NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q12.2
Genomic location:
Preferred name:
NM_000268.4(NF2):c.104T>G (p.Phe35Cys)
HGVS:
  • NC_000022.11:g.29604102T>G
  • NG_009057.1:g.5547T>G
  • NM_000268.4:c.104T>GMANE SELECT
  • NM_001407053.1:c.-127T>G
  • NM_001407054.1:c.104T>G
  • NM_001407055.1:c.104T>G
  • NM_001407056.1:c.-127T>G
  • NM_001407057.1:c.104T>G
  • NM_001407058.1:c.104T>G
  • NM_001407059.1:c.104T>G
  • NM_001407060.1:c.104T>G
  • NM_001407062.1:c.104T>G
  • NM_001407063.1:c.104T>G
  • NM_001407064.1:c.104T>G
  • NM_001407065.1:c.-537T>G
  • NM_001407066.1:c.104T>G
  • NM_001407067.1:c.-153T>G
  • NM_016418.5:c.104T>G
  • NM_181825.3:c.104T>G
  • NM_181828.3:c.104T>G
  • NM_181829.3:c.104T>G
  • NM_181830.3:c.104T>G
  • NM_181831.3:c.104T>G
  • NM_181832.3:c.104T>G
  • NM_181833.3:c.104T>G
  • NP_000259.1:p.Phe35Cys
  • NP_000259.1:p.Phe35Cys
  • NP_001393983.1:p.Phe35Cys
  • NP_001393984.1:p.Phe35Cys
  • NP_001393986.1:p.Phe35Cys
  • NP_001393987.1:p.Phe35Cys
  • NP_001393988.1:p.Phe35Cys
  • NP_001393989.1:p.Phe35Cys
  • NP_001393991.1:p.Phe35Cys
  • NP_001393992.1:p.Phe35Cys
  • NP_001393993.1:p.Phe35Cys
  • NP_001393995.1:p.Phe35Cys
  • NP_057502.2:p.Phe35Cys
  • NP_861546.1:p.Phe35Cys
  • NP_861966.1:p.Phe35Cys
  • NP_861967.1:p.Phe35Cys
  • NP_861968.1:p.Phe35Cys
  • NP_861969.1:p.Phe35Cys
  • NP_861970.1:p.Phe35Cys
  • NP_861971.1:p.Phe35Cys
  • LRG_511t1:c.104T>G
  • LRG_511t2:c.104T>G
  • LRG_511:g.5547T>G
  • LRG_511p1:p.Phe35Cys
  • LRG_511p2:p.Phe35Cys
  • NC_000022.10:g.30000091T>G
  • NM_000268.3:c.104T>G
  • NR_156186.2:n.470T>G
  • NR_176267.1:n.470T>G
Protein change:
F35C
Molecular consequence:
  • NM_001407053.1:c.-127T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407056.1:c.-127T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407065.1:c.-537T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407067.1:c.-153T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000268.4:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407054.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407055.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407057.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407058.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407059.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407060.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407062.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407063.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407064.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407066.1:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016418.5:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181825.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181828.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181829.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181830.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181831.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181832.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181833.3:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_176267.1:n.470T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Neurofibromatosis, type 2 (SWNV)
Synonyms:
NF 2; Neurofibromatosis central type; Acoustic schwannomas bilateral; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007039; MedGen: C0027832; Orphanet: 637; OMIM: 101000

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004434877Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(May 24, 2023) 		germlineclinical testing

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

SCV004833079All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(May 4, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical 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 Invitae, SCV004434877.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 35 of the NF2 protein (p.Phe35Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. 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 NF2 protein function. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004833079.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This missense variant replaces phenylalanine with cysteine at codon 35 of the NF2 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 NF2-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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: May 7, 2024