Submissions for variant NM_030662.4(MAP2K2):c.603C>T (p.Leu201=)

gnomAD frequency: 0.00072  dbSNP: rs148291450

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000466681	SCV000616575	benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.603C>T (p.Leu201=) variant in the MAP2K2 gene is 0.191% (18/6102) of African 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	RCV000039489	SCV000063177	likely benign	not specified	2009-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000466681	SCV000561667	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039489	SCV000917612	benign	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.603C>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 was observed with an allele frequency of 0.00028 in 265334 control chromosomes (gnomAD). The observed variant frequency within African control individuals in the gnomAD database is approximately 920-folds higher than 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 origin. To our knowledge, no occurrence of c.603C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with other pathogenic variant has been reported (PTPN11 c.182A>G, p.Asp61Gly) in an internal specimen, providing supporting evidence for a benign role. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001705635	SCV001860429	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813315	SCV002060580	likely benign	Noonan syndrome and Noonan-related syndrome	2019-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705635	SCV004698564	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MAP2K2: BS1
PreventionGenetics, part of Exact Sciences	RCV003894846	SCV004726235	benign	MAP2K2-related disorder	2019-06-19	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004018724	SCV005029129	likely benign	Cardiovascular phenotype	2024-03-14	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.