PIK3CA NM_006218.2:c.3140A>G, His1047Arg

"This variant has been reported in ClinVar as Pathogenic (25 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen Brain Malformations Variant Curation Expert Panel expert panel."

Error in OpenAI Consolidation. OncoKB: PIK3CAH1047RPIK3CAH1047RSomaticNCBI Gene:5290|Show additional gene information Variant OverviewPIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.The PIK3CA H1047R mutation is known to be oncogenic.Hide mutation effect description The PIK3CA H1047R mutation is located in the kinase domain in exon 21 of the protein (PMID: 16341083, 17376864, 22120714). This mutation has been found in various cancers, including breast, head and neck, lung, colorectal and endometrial cancers (PMID: 27126994, 25631445, 23787421, 25079552, 22960745, 22941189, 17376864, 23636398). Expression of this mutation in chicken embryonic fibroblasts, Ba/F3 cells and MCF10A breast cells and in a transgenic mouse model demonstrated that it is activating as measured by increased kinase activity, downstream pathway activation, cytokine- and factor-independent proliferation, colony growth in soft agar, invasion and in vivo glioblastoma tumor burden compared to wildtype PIK3CA (PMID: 17376864, 26627007, 16432179, 16322248, 31996845). Genetically engineered mouse models have shown that the PIK3CA H1047R mutation promotes tumor formation in breast, colon, ovarian and lung cancer and malignant mesothelioma (PMID: 22370636, 23940356, 22214849, 21822287, 21324922, 19029981, 31911549). Mutations at this position are predicted to constitutively activate the catalytic subunit of PI3K (p110α) by exposing the catalytic loop towards the plasma membrane where its substrate, PIP2, is found (PMID: 17376864, 20593314). Patients with breast cancer harboring this mutation achieved partial response (n=2) or stable disease (n=1) following treatment with the PI3Kα inhibitor, alpelisib (PMID: 27126994). In a phase III trial of palbociclib/fulvestrant for ER+, HER2− advanced breast cancer that had previously progressed on endocrine therapy, patients with PIK3CA alterations, including the H1047R mutation, were found at a significantly higher percentage in end-of-treatment samples as compared to pre-treatment samples, suggesting that this mutation may play a role in resistance to fulvestrant (PMID: 30206110). Preclinical studies with mice expressing PIK3CA H1047R demonstrated sensitivity to treatment with RLY-2608 as measured by reduced tumor volume following treatment (Abstract: Varkaris et al. Abstract# CT017, AACR 2023.). JAX-CKB: PIK3CA H1047R is a hotspot mutation that lies within the kinase domain of the Pik3ca protein (UniProt.org). H1047R results in increased phosphorylation of Akt and Mek1/2 and colony formation in culture (PMID: 26627007), and transformation in cell culture (PMID: 29533785, PMID: 17376864).