Submissions for variant NM_006218.4(PIK3CA):c.3073A>G (p.Thr1025Ala)

dbSNP: rs397517202

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038673	SCV000062351	pathogenic	Non-small cell lung carcinoma	2011-08-10	criteria provided, single submitter	clinical testing	The Thr1025Ala variant has been reported in the literature as a somatic change in several different tumor types (endometrium, thyroid, large intestine, pituitary, lung carcinoma; COSMIC). Somatic PIK3CA variants have been identified in up to 4% of cases of lung cancer (Samuels 2004).
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254274	SCV002525578	pathogenic	not provided	2022-03-03	criteria provided, single submitter	clinical testing	This variant has been reported in multiple cancer types and once in the literature in an individual with megalencephaly-capillary malformation (PMID: 22729224, PMID: 23982433). The p.Thr1025Ala variant substitute a threonine with an alanine in the kinase domain of the PIK3CA protein. Variants in this domain are typically activating (PMID: 18268322). This variant has also been observed in patient databases among individuals with cancer or PROS disorder, consisting of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi.
GeneDx	RCV002254274	SCV003842837	likely pathogenic	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23592320, 26453385, 16764926, 22997091, 19903786, 23982433, 34519764, 34858176, 35127508, 31217897, 22729224)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458194	SCV004176910	likely pathogenic	PIK3CA related overgrowth syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The PIK3CA c.3073A>G (p.Thr1025Ala) was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with capillary malformations (Rivière JB et al., PMID: 22729224; Mirzaa GM et al., PMID: 23592320; Mirzaa G et al., PMID: 27631024). This variant has been reported in the ClinVar database as a somatic pathogenic variant by multiple submitters and a germline likely pathogenic variant by one submitter (ClinVar ID: 45467). Additionally, it has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v3.1.2), indicating it is not a common variant. Another variant in the same codon, c.3074C>G (p.Thr1025Ser), has been reported in multiple cancer cases (Dhami J et al., PMID: 29588307; Gymnopoulos M et al., PMID: 17376864; ClinVar ID: 495324). The PIK3CA c.3073A>G (p.Thr1025Ala) variant resides within a catalytic domain, PI3Kc_IA_alpha, amino acids 695-1064, of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai et al., PMID: 35997716). However, functional studies that correlate with the impact of this variant on PIK3CA function is lacking. The PIK3CA gene is defined by ClinGen's Brain Malformation expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai et al, PMID: 35997716). A large number of PI3K/AKT pathway inhibitors are currently under clinical study in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.3073A>G (p.Thr1025Ala) variant is classified as likely pathogenic.
Medical Genetics Laboratory, Aldo Moro University of Bari	RCV001526503	SCV001736926	pathogenic	CLOVES syndrome	2021-06-06	no assertion criteria provided	clinical testing