Submissions for variant NM_030662.4(MAP2K2):c.170T>G (p.Phe57Cys)

dbSNP: rs121434497

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000208756	SCV000616538	pathogenic	Cardio-facio-cutaneous syndrome	2017-05-09	reviewed by expert panel	curation	The c.170T>G (p.Phe57Cys) variant in MAP2K2 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 16439621). In vitro functional studies provide some evidence that the p.Phe57Cys variant may impact protein function (PS3; PMID 16439621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of MAP2K2 (p.Phe57Val for malignant melanoma) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 8273). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS3, PM2, PM5, PP2, PM1, PP3.
GeneDx	RCV000158038	SCV000207973	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased kinase activity and activation of downstream effectors (PMID: 18413255); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 16439621, 19156172, 22177953, 22753777, 25370473, 26399658, 29493581, 18413255)
OMIM	RCV000008761	SCV000028970	pathogenic	Cardiofaciocutaneous syndrome 4	2008-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000208756	SCV000264641	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	literature only
GenomeConnect - CFC International	RCV000208756	SCV002047662	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	phenotyping only	Variant reported as having been "documented to be causative for CFC syndrome" and reported on 05-11-2006 by lab or GTR ID Prevention Genetics. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.