Submissions for variant NM_000268.4(NF2):c.713C>T (p.Ala238Val)

gnomAD frequency: 0.00001  dbSNP: rs761195572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701250	SCV000830041	uncertain significance	Neurofibromatosis, type 2	2022-02-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 238 of the NF2 protein (p.Ala238Val). This variant is present in population databases (rs761195572, gnomAD 0.0009%). 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: 578288). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV001026080	SCV001188391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-17	criteria provided, single submitter	clinical testing	The p.A238V variant (also known as c.713C>T), located in coding exon 8 of the NF2 gene, results from a C to T substitution at nucleotide position 713. The alanine at codon 238 is replaced by valine, an amino acid with similar properties. This alteration has been reported in an individual with hepatocellular carcinoma (Yoo NJ et al. Pathology, 2012 Jan;44:29-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000701250	SCV002044859	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV002305530	SCV002599550	uncertain significance	not provided	2023-12-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22081132, 11756419, 16324214)
Baylor Genetics	RCV003460968	SCV004199069	uncertain significance	Familial meningioma	2023-05-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000701250	SCV004821911	uncertain significance	Neurofibromatosis, type 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 238 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 been reported in one individual affected with hepatocellular carcinoma (PMID: 22081132). This variant has been identified in 1/251472 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.