Submissions for variant NM_002755.4(MAP2K1):c.370C>T (p.Pro124Ser)

dbSNP: rs1057519732

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001250385	SCV001424740	pathogenic	RASopathy	2020-07-02	reviewed by expert panel	curation	The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID: 22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser variant is located in the MAP2K1 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 MAP2K1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg 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): PS2_VeryStrong, PS3, PM1, PM2, PP2, PP3.
GeneDx	RCV000482718	SCV000572401	pathogenic	not provided	2020-10-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with a neurodevelopmental disorder to our knowledge; This variant is associated with the following publications: (PMID: 22197931, 32978145)
Mendelics	RCV000989347	SCV001139638	likely pathogenic	Cardiofaciocutaneous syndrome 3	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001250385	SCV003316958	uncertain significance	RASopathy	2023-04-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Pro124 amino acid residue in MAP2K1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17366577, 27862862, 28049852; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MAP2K1 function (PMID: 22197931, 26343583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP2K1 protein function. ClinVar contains an entry for this variant (Variation ID: 375981). This missense change has been observed in individual(s) with clinical features of cardio-facio-cutaneous syndrome (PMID: 32978145; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 124 of the MAP2K1 protein (p.Pro124Ser).
Database of Curated Mutations (DoCM)	RCV000433235	SCV000504542	pathogenic	Melanoma	2016-03-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444865	SCV000504543	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426713	SCV000504544	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433927	SCV000504545	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443916	SCV000504546	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000824936	SCV000965971	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing