rs1057519929
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_006218.4(PIK3CA):c.241G>A(p.Glu81Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PIK3CA
NM_006218.4 missense
NM_006218.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.36
Genes affected
PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88
PP5
Variant 3-179199066-G-A is Pathogenic according to our data. Variant chr3-179199066-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179199066-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PIK3CA | NM_006218.4 | c.241G>A | p.Glu81Lys | missense_variant | 2/21 | ENST00000263967.4 | NP_006209.2 | |
| PIK3CA | XM_006713658.5 | c.241G>A | p.Glu81Lys | missense_variant | 2/21 | XP_006713721.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PIK3CA | ENST00000263967.4 | c.241G>A | p.Glu81Lys | missense_variant | 2/21 | 2 | NM_006218.4 | ENSP00000263967 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2023 | 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: 28502730, 34758253, 25915946, 26619011, 23592320, 29549527, 27798902, 21531001, 29493003, 33539671, 34969754, 34779417, 32923889, 24037760, 33503190, 33442366, 30243889, 33105631, 32235312, 22729224, 29575851, 29643510, 34684076, 34736091, 34150029) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Dec 29, 2020 | This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31585106, PMID: 22729224, PMID: 25915946). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). The p.Glu81Lys replaces the glycine at codon 81 with lysine within the PI3K adaptor-binding domain of the protein (UniProt P42336). Experimental studies have demonstrated that the p.Glu81Lys variant causes overactivation of the PI3K/AKT/mTOR pathway (PMID: 25915946). - |
Glioblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Papillary renal cell carcinoma type 1 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Medulloblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
CLOVES syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Cowden syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2021 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 376478). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PMID: 22729224, 25915946). In at least one individual the variant was observed to be de novo. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PIK3CA protein (p.Glu81Lys). - |
Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
PIK3CA related overgrowth syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Sep 20, 2023 | The PIK3CA c.241G>A (p.Glu81Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by PROS disorders (Rivière JB et al., PMID: 22729224; Loconte DC et al., PMID: 25915946; Kuentz P et al., PMID: 28151489; Leiter SM et al., PMID: 28566443; Zhang M et al., PMID: 30996962; Mirzaa GM et al., PMID: 23592320; Denorme P et al., PMID: 29493003; Paolacci S et al., PMID: 33105631; Ranieri C et al., PMID: 29549527). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic by multiple submitters in both a somatic and germline state (ClinVar ID: 376478) and in multiple cases in the cancer database COSMIC (ID: COSV55873676). This variant is absent from the general population database (gnomAD v.3.1.2), indicating that it is not a common variant. This variant resides within a p85-binding domain, amino acids 32-107, of PIK3CA that is defined as a critical functional domain (Burke JE et al., PMID: 22949682; Zhang M et al., PMID: 30996962). Functional in vitro studies show that this variant induces Akt-mTOR signaling and enhanced cell growth, indicating that this variant impacts protein function (Jin N et al., PMID: 34779417; Loconte DC et al., PMID: 25915946). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. 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). 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.241G>A (p.Glu81Lys) variant is classified as pathogenic. - |
Malignant neoplasm of body of uterus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Abnormal cardiovascular system morphology Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Neoplasm of uterine cervix Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
D;.;.
Vest4
MutPred
Gain of methylation at E81 (P = 0.0034);Gain of methylation at E81 (P = 0.0034);Gain of methylation at E81 (P = 0.0034);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at