Submissions for variant NM_030662.4(MAP2K2):c.240G>A (p.Ala80=)

gnomAD frequency: 0.00004  dbSNP: rs543217722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000523706	SCV000616586	likely benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.240G>A (p.Ala80=) variant in the MAP2K2 gene is 0.0284% (9/16506) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
GeneDx	RCV000590354	SCV000515366	likely benign	not provided	2017-09-11	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590354	SCV000699633	benign	not provided	2016-03-21	criteria provided, single submitter	clinical testing	Variant summary: The c.240G>A variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts damaging outcome for this variant. 4/5 in silico programs via Alamut predict no significant change on RNA splicing sites. ESEfiner predicts changes of binding motifs for splicing enhancers. This variant is found in 10/120764 control chromosomes at a frequency of 0.0000828, predominalty observed in South Asian subpopulation in ExAC with MAF of 0.005453 (9/16506 chr), which significantly exceeds the maximal expected frequency of a pathogenic allele (0.0000025), suggesting this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523706	SCV000776888	likely benign	RASopathy	2023-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446659	SCV002734422	likely benign	Cardiovascular phenotype	2020-12-11	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.
PreventionGenetics, part of Exact Sciences	RCV003922721	SCV004745692	likely benign	MAP2K2-related disorder	2019-09-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).