Submissions for variant NM_030662.4(MAP2K2):c.525C>T (p.Ile175=)

gnomAD frequency: 0.00029  dbSNP: rs150833333

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000126671	SCV000616579	benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.525C>T (p.Ile175=) variant in the MAP2K2 gene is 0.255% (11/2418) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039487	SCV000063175	likely benign	not specified	2009-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000039487	SCV000170180	benign	not specified	2012-01-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000126671	SCV000260507	likely benign	RASopathy	2024-01-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000039487	SCV000314692	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039487	SCV000919605	benign	not specified	2018-02-26	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.525C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 252824 control chromosomes. The observed variant frequency is approximately 98.092 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.525C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813366	SCV002060578	benign	Noonan syndrome and Noonan-related syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336140	SCV002643345	likely benign	Cardiovascular phenotype	2022-04-23	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.