The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_030662.3(MAP2K2):c.170T>G (p.Phe57Cys)

CA279958

8272 (ClinVar)

Gene: MAP2K2
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 07aecf91-9cf2-48c7-b101-b21e809f57a4

HGVS expressions

NM_030662.3:c.170T>G
NM_030662.3(MAP2K2):c.170T>G (p.Phe57Cys)
ENST00000262948.9:c.170T>G
ENST00000394867.8:c.-122T>G
ENST00000599345.1:n.367T>G
NC_000019.10:g.4117552A>C
CM000681.2:g.4117552A>C
NC_000019.9:g.4117550A>C
CM000681.1:g.4117550A>C
NC_000019.8:g.4068550A>C
NG_007996.1:g.11577T>G

Pathogenic

Met criteria codes 7
PS3 PP3 PP2 PM5 PM1 PM6 PM2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
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.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.Phe57Cys variant may impact protein function (PS3; PMID 16439621).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
The variant is in MAP2K2, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581).
PM5
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).
PM1
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).
PM6
The 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).

PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2017-05-09
Published on: 2018-12-10
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