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: 2
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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 2023-04-06 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. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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