Submissions for variant NM_030662.4(MAP2K2):c.844C>T (p.Pro282Ser)

gnomAD frequency: 0.00070  dbSNP: rs142307980

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000522371	SCV000616548	benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.844C>T (p.Pro282Ser) variant in the MAP2K2 gene is 0.029% for African chromosomes by the Exome Aggregation Consortium (19/6048 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's 26957; SCV000207963.8). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039495	SCV000063184	likely benign	not specified	2015-09-29	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000680293	SCV000207963	benign	not provided	2016-06-03	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	RCV000522371	SCV001003111	likely benign	RASopathy	2024-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039495	SCV001363494	benign	not specified	2019-07-08	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.844C>T (p.Pro282Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 263182 control chromosomes including one homozygote, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 720 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.844C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions including one expert panel (ClinGen RASopathy Variant Curation) (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV003343604	SCV004051623	likely benign	Cardiovascular phenotype	2023-06-16	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.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000824950	SCV000965985	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944871	SCV004763576	likely benign	MAP2K2-related disorder	2021-07-01	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).