Submissions for variant NM_030662.4(MAP2K2):c.825G>A (p.Leu275=)

gnomAD frequency: 0.00007  dbSNP: rs587781027

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000524027	SCV000616569	benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.825G>A (p.Leu275=) variant in the MAP2K2 gene is 0.142% (14/5968) of East Asian 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)
GeneDx	RCV000126677	SCV000170186	benign	not specified	2013-12-06	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	RCV000589791	SCV000699644	benign	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The MAP2K2 c.825G>A (p.Leu275Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, and 4/5 splicing algorithms predict no significant change to normal splicing. This variant was found in 14/79364 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0023458 (14/5968). This frequency is about 938 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), highly suggesting this is a benign polymorphism found primarily in the populations of East Asian origin. In addition, the variant has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Furthermore, one clinical diagnostic laboratory classified this variant as benign. Taken together and based on the high allele frequency in the East Asian ExAC population, this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524027	SCV001673724	likely benign	RASopathy	2024-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426686	SCV002681886	likely benign	Cardiovascular phenotype	2022-03-07	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	RCV003965051	SCV004782118	likely benign	MAP2K2-related disorder	2020-10-02	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).