Submissions for variant NM_030662.4(MAP2K2):c.1140C>T (p.Ala380=)

gnomAD frequency: 0.00034  dbSNP: rs146618055

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000521790	SCV000616562	likely benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.1140C>T (p.Ala380=) variant in the MAP2K2 gene is 0.003% (2/796) of East 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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043643	SCV000063156	likely benign	not specified	2012-10-18	criteria provided, single submitter	clinical testing	Ala380Ala in exon 11 of MAP2K2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located ne ar a splice junction. In addition, this variant was identified via high-throughp ut sequencing in controls (MAF<1%) and presumed to be benign (Kelleher 2012).
GeneDx	RCV000043643	SCV000207953	benign	not specified	2014-08-26	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.
Invitae	RCV000521790	SCV001000776	benign	RASopathy	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043643	SCV001363490	benign	not specified	2019-03-18	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.1140C>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 0.00023 in 192890 control chromosomes. The observed variant frequency is approximately 93 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.1140C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One expert panel has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Two other labs in ClinVar classified the variant as benign and likely benign respectively in 2014. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813371	SCV002060568	benign	Noonan syndrome and Noonan-related syndrome	2020-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002460041	SCV002618414	benign	Cardiovascular phenotype	2020-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV003944960	SCV004762028	likely benign	MAP2K2-related condition	2019-10-23	criteria provided, single submitter	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).