Submissions for variant NM_030662.4(MAP2K2):c.289A>T (p.Ile97Phe)

gnomAD frequency: 0.00004  dbSNP: rs373579939

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039477	SCV000063162	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ile97Phe vari ant in MAP2K2 has now been identified by our laboratory in 2 individuals with cl inical features of a RASopathy disorder and a reportedly unaffected parent. It h as also been identified in 1/65212 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373579939). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. In summary, although the clinical significance of the p.Ile97Phe variant is uncertain, identification in an unaffected parent suggest that this variant i s more likely benign.
GeneDx	RCV000767153	SCV000207978	uncertain significance	not provided	2014-01-06	criteria provided, single submitter	clinical testing	This variant is denoted c.289 A>T at the cDNA level or p.Ile97Phe (I97F) at the protein level. The I97F missense change has not been previously reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. The I97F missense change is a conservative amino acid substitution as both Isoleucine and Phenylalanine are neutral and non-polar resiudes. The residue at which this substitution occurs is conserved in mammals. The I97F variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In silico models are discordant in their assessment of the pathogenicity of the variant. Another missense mutation at a nearby residue (A80T) has been reported. Although the majority of missense changes in MAP2K2 are pathogenic mutations, the potential for benign coding variants to exist in this gene must be considered. The variant is found in NOONAN panel(s).
Invitae	RCV000545526	SCV000659162	uncertain significance	RASopathy	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 97 of the MAP2K2 protein (p.Ile97Phe). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt MAP2K2 function. ClinVar contains an entry for this variant (Variation ID: 46232). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. This variant is present in population databases (rs373579939, gnomAD 0.002%). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000767153	SCV002501006	uncertain significance	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000767153	SCV004224526	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	PP3