PIK3CA NM_006218.2:c.2740G>A, Gly914Arg

This variant has been previously reported as disease-causing and was found twice in our laboratory in individuals with overgrowth, macrocephaly, hemihypertrophy, and polydactyly or syndactyly

The c.2740G>A (p.G914R) alteration is located in exon 19 (coding exon 18) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 2740, causing the glycine (G) at amino acid position 914 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported as a de novo occurrence and heterozygous in multiple individuals with megalencephaly, overgrowth, vascular malformations and/or other clinical features consistent with PIK3CA-related disorders; this variant was detected in multiple sample types for some individuals (Rivière, 2012; Mirzaa, 2016; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The c.2740G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Gly914Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; identified in 5 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), and in 4 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and it was identified in 2 tumor samples in COSMIC (PMID: 22729224, PMID: 28151489, PMID: 28502725, PMID: 30231930). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; 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, PP2, PM1_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021)