ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1055C>T (p.Thr352Met)

gnomAD frequency: 0.00003  dbSNP: rs764441073
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690349 SCV000818031 uncertain significance Neurofibromatosis, type 2 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 352 of the NF2 protein (p.Thr352Met). This variant is present in population databases (rs764441073, gnomAD 0.003%). This missense change has been observed in individual(s) with neurofibromatosis type 2 (NF2), osteosarcoma, as well as unaffected individuals (PMID: 8081368, 32191290; Invitae). ClinVar contains an entry for this variant (Variation ID: 569661). 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: 10712203, 11779178). 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 RCV002406553 SCV002715516 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-12 criteria provided, single submitter clinical testing The p.T352M variant (also known as c.1055C>T), located in coding exon 11 of the NF2 gene, results from a C to T substitution at nucleotide position 1055. The threonine at codon 352 is replaced by methionine, an amino acid with similar properties. The variant has been reported to be de novo in one individual with neurofibromatosis 2 (NF2) and detected in another individual with bilateral vestibular schwannomas (Evans DG et al. J Med Genet, 1992 Dec;29:841-6; Bourn D et al. Hum. Mol. Genet., 1994 May;3:813-6). However, this variant has been identified in multiple individuals without clinical features of NF2 (Ambry internal data). Functional studies have shown that the variant may affect some aspects of the NF2 protein function; however, most of the functions are unaffected and clinical relevance of these studies is unknown (Stokowski RP et al. Am J Hum Genet, 2000 Mar;66:873-91; Gutmann DH et al. Hum Mol Genet, 2001 Jul;10:1519-29; Scoles DR et al. Biochem Biophys Res Commun, 2002 Jan;290:366-74). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health RCV000690349 SCV004821914 uncertain significance Neurofibromatosis, type 2 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 352 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 have reported that the variant protein behaved similar to wild-type protein expressed in ex vivo cultured cells in protein expression, protein-protein interaction, subcellular localization, cell proliferation and actin cytoskeleton associated activity assays (PMID: 10712203, 11448944). This variant has been reported in an individual affected with type 2 neurofibromatosis (PMID: 8081368). This variant has been identified in 3/251460 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.
Baylor Genetics RCV004569293 SCV005052360 uncertain significance Familial meningioma 2024-03-24 criteria provided, single submitter clinical testing

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