Submissions for variant NM_000268.4(NF2):c.296A>G (p.Lys99Arg)

gnomAD frequency: 0.00001  dbSNP: rs181794923

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806495	SCV000946499	uncertain significance	Neurofibromatosis, type 2	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 99 of the NF2 protein (p.Lys99Arg). This variant is present in population databases (rs181794923, gnomAD 0.009%). 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: 651188). 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. 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	RCV001017700	SCV001178822	benign	Hereditary cancer-predisposing syndrome	2021-12-17	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.
Genome-Nilou Lab	RCV000806495	SCV002044841	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001017700	SCV002528191	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000806495	SCV004824784	uncertain significance	Neurofibromatosis, type 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 99 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251468 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	RCV004723217	SCV005340626	uncertain significance	NF2-related disorder	2024-07-19	no assertion criteria provided	clinical testing	The NF2 c.296A>G variant is predicted to result in the amino acid substitution p.Lys99Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain and benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/651188/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.