Submissions for variant NM_000268.4(NF2):c.1619A>G (p.Asn540Ser)

gnomAD frequency: 0.00004  dbSNP: rs774824164

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685036	SCV000812507	uncertain significance	Neurofibromatosis, type 2	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the NF2 protein (p.Asn540Ser). This variant is present in population databases (rs774824164, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 565467). 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%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765630	SCV000896955	uncertain significance	Familial meningioma; Neurofibromatosis, type 2; Schwannomatosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001012452	SCV001172904	likely benign	Hereditary cancer-predisposing syndrome	2020-12-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Genome-Nilou Lab	RCV000685036	SCV002044904	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001012452	SCV002528186	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000685036	SCV004827731	uncertain significance	Neurofibromatosis, type 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 540 of the NF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with NF2-related disorders in the literature. This variant has been identified in 4/282856 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.