Submissions for variant NM_000268.4(NF2):c.1540A>G (p.Met514Val)

gnomAD frequency: 0.00009  dbSNP: rs201527155

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203209	SCV000258269	uncertain significance	Neurofibromatosis, type 2	2015-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV000203209	SCV000553674	uncertain significance	Neurofibromatosis, type 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 514 of the NF2 protein (p.Met514Val). This variant is present in population databases (rs201527155, gnomAD 0.02%). This missense change has been observed in individual(s) with bilateral vestibular schwannomas and/or breast cancer (PMID: 16983642, 35264596). ClinVar contains an entry for this variant (Variation ID: 201125). 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 not expected to disrupt NF2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NF2 function (PMID: 26045165). 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.
Ambry Genetics	RCV000565248	SCV000674131	benign	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	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.
Mendelics	RCV000203209	SCV000839526	uncertain significance	Neurofibromatosis, type 2	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203209	SCV001306002	benign	Neurofibromatosis, type 2	2018-01-13	criteria provided, single submitter	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001812175	SCV002011410	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000203209	SCV002045415	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812175	SCV002048964	uncertain significance	not provided	2021-04-13	criteria provided, single submitter	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.
Sema4, Sema4	RCV000565248	SCV002528184	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003462289	SCV004199033	uncertain significance	Familial meningioma	2023-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000203209	SCV004357042	uncertain significance	Neurofibromatosis, type 2	2023-05-09	criteria provided, single submitter	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.
PreventionGenetics, part of Exact Sciences	RCV003955108	SCV004768943	uncertain significance	NF2-related disorder	2024-01-22	criteria provided, single submitter	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.
All of Us Research Program, National Institutes of Health	RCV000203209	SCV004821918	uncertain significance	Neurofibromatosis, type 2	2023-12-18	criteria provided, single submitter	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.