ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs201527155
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Total submissions: 11
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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: 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.

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