ClinVar

Description

This sequence change in PIK3CA is predicted to replace arginine with histidine at codon 38, p.(Arg38His). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in adaptor binding domain (PI3K ABD) a region, amino acids 31-108, that is defined as a mutational hotspot. There is a small physicochemical difference between arginine and histidine. PIK3CA , in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0002% (2/1,110,018 alleles) in the European (non-Finnish) population. This variant has been detected in at least one individual with polymicrogyria (Melbourne Health Pathology) and has been reported as a somatic event in at least 40 tumour samples (COSMIC ID: COSV55879949). In vitro functional studies assessing kinase activity (with limited assay validation) demonstrate a gain of function effect for the variant which is weaker than well-established pathogenic gain of function variants (PMID: 15930273, 16339315, 17376864). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.654). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1_Supporting, PM2_Supporting, PP2, PP3, PS3_Supporting.