rs104886003

Variant names:

• chr3-179218303-G-A
• rs104886003
• NM_006218.4:c.1633G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-179218303-G-A
• chr3-179218303-G-C
• chr3-179218303-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1633G>A​(p.Glu545Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 O:3
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain PIK helical (size 177) in uniprot entity PK3CA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.871
• PP5: Variant 3-179218303-G-A is Pathogenic according to our data. Variant chr3-179218303-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179218303-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1633G>A	p.Glu545Lys	missense_variant	Exon 10 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1633G>A	p.Glu545Lys	missense_variant	Exon 10 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1633G>A	p.Glu545Lys	missense_variant	Exon 10 of 21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247990 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4 -

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); 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: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224) -

CLOVES syndrome Pathogenic:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PIK3CA related overgrowth syndrome Pathogenic:2

Jan 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 01, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the helical domain of the p110⍺ catalytic subunit, amino acids 517-694, of PIK3CA that is defined as a critical functional domain, and constitutes a mutational hotspot (Madsen R et al., PMID: 30197175; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A 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.1633G>A (p.Glu545Lys) variant is classified as pathogenic. -

Non-small cell lung carcinoma Pathogenic:2

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 29, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Seborrheic keratosis Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Segmental undergrowth associated with lymphatic malformation Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMIFACIAL MYOHYPERPLASIA, SOMATIC Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Eccrine angiomatous hamartoma Pathogenic:1

Oct 21, 2021

Genomics For Life

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant. -

Gastric cancer Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

OVARIAN CANCER, EPITHELIAL, SOMATIC Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rare venous malformation Pathogenic:1

Mar 19, 2024

Institute of Tissue Medicine and Pathology, University of Bern

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast adenocarcinoma Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Gallbladder cancer Pathogenic:1

Oct 30, 2020

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cerebrofacial Vascular Metameric Syndrome (CVMS) Pathogenic:1

Sep 30, 2021

James Bennett Lab, Seattle Childrens Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Carcinoma of colon Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PIK3CA overgrowth syndrome Pathogenic:1

Dec 09, 2020

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007). -

Abnormal cardiovascular system morphology Pathogenic:1

-

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Rare combined vascular malformation Pathogenic:1

Mar 19, 2024

Institute of Tissue Medicine and Pathology, University of Bern

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Angioosteohypertrophic syndrome Pathogenic:1

Mar 19, 2024

Institute of Tissue Medicine and Pathology, University of Bern

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sarcoma Other:1

-

Laboratory of Translational Genomics, National Cancer Institute

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.069	T;.
Polyphen		0.99	D;.
Vest4		0.96
MutPred		0.73		Gain of methylation at E545 (P = 0.0068);Gain of methylation at E545 (P = 0.0068);
MVP		0.93
MPC		2.8
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886003; hg19: chr3-178936091; COSMIC: COSV55873239; COSMIC: COSV55873239;