Submissions for variant NM_000268.4(NF2):c.613A>G (p.Met205Val)

gnomAD frequency: 0.00016  dbSNP: rs141629512

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234683	SCV000284554	benign	Neurofibromatosis, type 2	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455031	SCV000539888	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 or 3 probands
Ambry Genetics	RCV000565164	SCV000674134	benign	Hereditary cancer-predisposing syndrome	2021-05-21	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.
Mendelics	RCV000234683	SCV000839515	uncertain significance	Neurofibromatosis, type 2	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001706246	SCV001825051	likely benign	not provided	2024-02-05	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Genome-Nilou Lab	RCV000234683	SCV002045400	likely benign	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455031	SCV003800705	likely benign	not specified	2023-01-12	criteria provided, single submitter	clinical testing	Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282888 control chromosomes (gnomAD), predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis Type 2 phenotype (1.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000234683	SCV004821910	uncertain significance	Neurofibromatosis, type 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 205 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 two individuals affected with multiple meningiomas or Neurofibromatosis type 2 (PMID: 15635074, 26073919). This variant has been identified in 24/282888 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.