Submissions for variant NM_030662.4(MAP2K2):c.581-8G>A

gnomAD frequency: 0.00012  dbSNP: rs369262004

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216682	SCV000270398	likely benign	not specified	2015-02-25	criteria provided, single submitter	clinical testing	c.581-8G>A in intron 5 of MAP2K2: This variant is not expected to have clinical significance because a change at this position does not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. Furthermore, sp lice variants are not a known mechanism of disease for Noonan syndrome. It has b een identified in 5/67874 ethnically diverse chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369262004).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216682	SCV000699639	benign	not specified	2020-10-01	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.581-8G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 8.1e-05 in 234782 control chromosomes. The observed variant frequency is approximately 32 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. c.581-8G>A has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (example, Justino_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001722158	SCV000728673	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing
Invitae	RCV001442552	SCV001645503	likely benign	RASopathy	2023-12-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003741165	SCV004564312	benign	Cardiofaciocutaneous syndrome 4	2023-01-26	criteria provided, single submitter	clinical testing