NM_006218.4:c.1624G>A

Variant names:

• chr3-179218294-G-A
• rs121913273
• NM_006218.4:c.1624G>A
• PIK3CA p.Glu542Lys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 25 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_Very_StrongO3_ModerateO4_ModerateO7_StrongO8_Supporting

The NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The gene PIK3CA is a known oncogene (CancerMine: 3 TSG, 156 oncogene, 103 driver citations). The gene PIK3CA is a cancer driver gene (CancerMine: 3 TSG, 156 oncogene, 103 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002525701: "This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID:26627007)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.E542G: Likely_pathogenic (ClinVar VariationId 376475, 2 stars) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 372 samples carry this exact amino acid change out of 1860 samples with a variant at this residue. The variant has been observed in cBioPortal in 4206 samples across 202 studies and 192 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:21 O:8
• Conservation: PhyloP100: 9.60
• Publications: 2431 publications found

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]

PIK3CA Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 25 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		Variant on SVIG-UK Canonical Variants List — Stand-alone Oncogenic (O1); ClinVar oncogenic/SCI T1 (expert panel/practice guideline, ★★★+) — Very Strong (O1); ClinVar oncogenic/SCI T1 (multiple submitters, ★★) — Strong (O1); ClinVar oncogenic/SCI T1 (single/no review, ★0–1) — Moderate (O1); O1 contributing sources (16.0 pts): SVIG-UK Canonical Variants List, ClinVar (somatic oncogenic/LO (★★★)), CGI (Cancer Genome Interpreter)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=4206 | studies=202 | cancer types=192 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 1860, same AA change = 372; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 19 pathogenic, 1 benign (OR vs. background: 65.0).; ±8 AA neighbourhood: 13 pathogenic, 0 benign (OR vs. background: 135.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 6.15 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA NM_006218.4	MANE Select	c.1624G>A p.Glu542Lys	missense	Exon 10 of 21	Prot: NP_006209.2 UniProt:

PIK3CA NM_006218.4

MANE Select

HGVSc / HGVSpc.1624G>Ap.Glu542Lys

Exon rankExon 10 of 21

missense

Prot: NP_006209.2UniProt: P42336

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PIK3CA ENST00000263967.4	TSL:2MANE Select	c.1624G>A p.Glu542Lys	missense	Exon 10 of 21	Prot: ENSP00000263967.3 UniProt:
	PIK3CA ENST00000955190.1		c.1654G>A p.Glu552Lys	missense	Exon 10 of 21	Prot: ENSP00000625249.1 UniProt:
	PIK3CA ENST00000876545.1		c.1624G>A p.Glu542Lys	missense	Exon 11 of 22	Prot: ENSP00000546604.1 UniProt:

PIK3CA ENST00000263967.4

TSL:2MANE Select

HGVSc / HGVSpc.1624G>Ap.Glu542Lys

Exon rankExon 10 of 21

missense

Prot: ENSP00000263967.3UniProt: P42336

PIK3CA ENST00000955190.1

HGVSc / HGVSpc.1654G>Ap.Glu552Lys

Exon rankExon 10 of 21

missense

Prot: ENSP00000625249.1UniProt: A0ACI8UU87

PIK3CA ENST00000876545.1

HGVSc / HGVSpc.1624G>Ap.Glu542Lys

Exon rankExon 11 of 22

missense

Prot: ENSP00000546604.1UniProt: P42336

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13774	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	CLOVES syndrome (3)
3	-	-	not provided (3)
2	-	-	Ovarian neoplasm (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC (1)
1	-	-	Cerebrofacial Vascular Metameric Syndrome (CVMS) (1)
1	-	-	CLAPO syndrome (1)
1	-	-	Cowden syndrome (1)
1	-	-	HEMIFACIAL MYOHYPERPLASIA, SOMATIC (1)
1	-	-	Lip and oral cavity carcinoma (1)
1	-	-	Megalencephaly-capillary malformation-polymicrogyria syndrome (1)
1	-	-	Non-small cell lung carcinoma (1)
1	-	-	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (1)
1	-	-	PIK3CA related overgrowth syndrome (1)
1	-	-	PIK3CA-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-8.9
GPN-Star score	N/A	8.9
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.73	T
Mutation Taster	N/A	6/94	disease causing (ClinVar)
MutationAssessor	Benign	1.7	L
PhyloP100	Pathogenic	9.6
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.016	D
Sift4G	Benign	0.10	T
Varity_R	N/A	0.90
VESM-3B	Benign	-8.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121913273;

hg19: chr3-178936082;

COSMIC: COSV55873227;

COSMIC: COSV55873227;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar