rs104886003

chr3-179218303-G-Achr3-179218303-G-Cchr3-179218303-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E545D) has been classified 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:51 O:2
• 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 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179218305-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• 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/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1633G>A	p.Glu545Lys	missense_variant	10/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1633G>A	p.Glu545Lys	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1633G>A	p.Glu545Lys	missense_variant	10/21	2	NM_006218.4	P1

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:51 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Dec 09, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4 -

Non-small cell lung carcinoma Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 29, 2009	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -

CLOVES syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

PIK3CA related overgrowth syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 01, 2023	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. -

Neoplasm of ovary Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

HEMIFACIAL MYOHYPERPLASIA, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Breast neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Eccrine Angiomatous Hamartoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics For Life

Oct 21, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

OVARIAN CANCER, EPITHELIAL, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Rare venous malformation Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Cerebrofacial Vascular Metameric Syndrome (CVMS) Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

James Bennett Lab, Seattle Childrens Research Institute

Sep 30, 2021

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Nasopharyngeal neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma 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

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Small cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Seborrheic keratosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Papillary renal cell carcinoma, sporadic Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Segmental undergrowth associated with lymphatic malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Apr 06, 2021

- -

Papillary renal cell carcinoma type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gallbladder cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Oct 30, 2020

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gallbladder carcinoma 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

-

- -

Rare combined vascular malformation Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder 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

- -

Angioosteohypertrophic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Sarcoma Other:1

not provided, no classification provided

literature only

Laboratory of Translational Genomics, National Cancer Institute

-

- -

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;.
MutationTaster	Benign	1.0	D
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;