ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.113G>A (p.Arg38His)

dbSNP: rs772110575
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV003993951 SCV004812709 likely pathogenic Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2024-04-07 criteria provided, single submitter clinical testing 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.
Database of Curated Mutations (DoCM) RCV000424742 SCV000507084 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431951 SCV000507085 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443605 SCV000507086 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425403 SCV000507087 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436118 SCV000507088 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418734 SCV000507089 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only

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