The c.1117G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Gly373Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the PIK3R2 SH2, sequence homology 2 domain of PIK3R2 that is defined as a critical functional domain by the ClinGen BMEP (PMID: 26860062) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in 2 individuals with macrocephaly (>=2 SD) and Developmental Delay or Intellectual disability with cortical malformation, 13 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and has been identified in over 15 tumor samples in the literature and COSMIC (PMID: 28086757,22729224, 28502725)). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID: 22729224). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PM1_P, PS4_VS, PS2_M; 13 points (VCEP specifications version 1; Approved: 1/31/2021)