22-29678289-A-G

Variant names:

• chr22-29678289-A-G
• rs201527155
• NM_000268.4:c.1540A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000268.4(NF2):​c.1540A>G​(p.Met514Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M514I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:3
• Conservation: PhyloP100: 7.32
• Publications: 9 publications found

Genes affected

NF2 (HGNC:7773): (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that link cytoskeletal components with proteins in the cell membrane. The encoded protein is involved in regulation of contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling. The encoded protein has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics, and proteins involved in regulating ion transport. Disruption of this protein's function has been implicated in tumorigenesis and metastasis. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. [provided by RefSeq, May 2022]

NF2 Gene-Disease associations (from GenCC):

• NF2-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2284613).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000919 (14/152322) while in subpopulation AMR AF = 0.000392 (6/15302). AF 95% confidence interval is 0.00017. There are 1 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 14 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.1540A>G	p.Met514Val	missense	Exon 14 of 16	NP_000259.1
	NF2	NM_001407066.1		c.1540A>G	p.Met514Val	missense	Exon 14 of 17	NP_001393995.1
	NF2	NM_016418.5		c.1540A>G	p.Met514Val	missense	Exon 14 of 17	NP_057502.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.1540A>G	p.Met514Val	missense	Exon 14 of 16	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.1540A>G	p.Met514Val	missense	Exon 14 of 17	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.1540A>G	p.Met514Val	missense	Exon 14 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251494 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000140 AC: 156 AN: 1111940

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 2 Uncertain:7 Benign:2

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 13, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF2 c.1540A>G (p.Met514Val) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function. Functional studies suggest that the variant protein alters the in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165). This variant has been reported in an individual with bilateral vestibular schwannomas (PMID: 16983642). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Oct 15, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A NF2 c.1540A>G (p.Met514Val) variant was identified at a near heterozygous allelic fraction of 49.18%, a frequency that may be consistent with germline origin. This variant, to our knowledge, has been reported as germline in at least two patients with schwannomas (Louvrier C et al., PMID:29409008). This variant is observed on 192/1614122 alleles in the general population with one homozygote (gnomAD v.4.1.0). This variant has been reported in the ClinVar database a variant of uncertain significance by multiple submitters and as a benign variant by two submitters, in a germline state if known (Clinvar ID: 201125). Computational predictors suggest that the variant may impact NF2 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the NF2 c.1540A>G (p.Met514Val) variant is uncertain at this time.

Jun 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 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.

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 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.

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF2 c.1540A>G; p.Met514Val variant (rs201527155) is reported in the literature in an individual with bilateral vestibular schwannoma, but was not determined to be causative (Ahronowitz 2007). The variant is reported in the ClinVar database (Variation ID: 201125) and is reported in the general population with an overall allele frequency of 0.0099% (28/282,872 alleles) in the Genome Aggregation Database. The methionine at codon 514 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of the p.Met514Val variant is uncertain at this time. Gene Statement: References: Ahronowitz I et al. Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007 Jan;28(1):1-12. PMID: 16983642.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Oct 22, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 27, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

NF2-related disorder Uncertain:1

Jan 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF2 c.1540A>G variant is predicted to result in the amino acid substitution p.Met514Val. This variant was reported in an individual with bilateral vestibular schwannomas; however, pathogenicity was not established (Ahronowitz et al 2007. PubMed ID: 16983642). This variant was also reported as a variant of uncertain significance in a large study of Brazilian breast cancer patients (Supp Table 3 in Guindalini RSC et al 2022. PubMed ID: 35264596). This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD, which is likely too common for an autosomal dominant disorder. This variant is reported in ClinVar with conflicting interpretations of uncertain and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/201125/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Familial meningioma Uncertain:1

Oct 17, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.037
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.66
Sift	Benign	0.27	T
Sift4G	Benign	0.62	T
Polyphen		0.0030	B
Vest4		0.59
MVP		0.97
MPC		0.83
ClinPred		0.066	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.34
gMVP		0.55
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201527155; hg19: chr22-30074278;