chr3-179218304-A-C

Variant names:

• chr3-179218304-A-C
• rs121913274
• NM_006218.4:c.1634A>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1634A>C​(p.Glu545Ala) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E545Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.95
• Publications: 541 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 Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 217293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 3-179218304-A-C is Pathogenic according to our data. Variant chr3-179218304-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.1634A>C	p.Glu545Ala	missense	Exon 10 of 21	NP_006209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.1634A>C	p.Glu545Ala	missense	Exon 10 of 21	ENSP00000263967.3
	PIK3CA	ENST00000643187.1		c.1634A>C	p.Glu545Ala	missense	Exon 10 of 22	ENSP00000493507.1
	PIK3CA	ENST00000462255.2	TSL:3	n.96A>C		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247982 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PIK3CA related overgrowth syndrome Pathogenic:1

Aug 01, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.1634A>C (p.Glu545Ala) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in individuals with lymphatic malformation, angiolipoma and Cowden-like syndrome (Orloff MS et al., PMID: 23246288; Osborn AJ et al., PMID: 25292196; Saggini A et al., PMID: 32662895) and in numerous individuals with cancer (Castaneda CA et al., PMID: 25467032; Fantappiè G et al., PMID: 32796408; Kommineni N et al., PMID: 25563369; Kwon MJ et al., PMID: 26054797; Liang X et al., PMID: 16582596; Zhu YF et al., PMID: 22851869). The PIK3CA c.1634A>C (p.Glu545Ala) has been reported in the ClinVar database as a germline pathogenic variant by a single submitter (ClinVar Variation ID: 13659). This variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. This variant resides within the helical domain of the p110α catalytic subunit of PIK3CA and constitutes a mutation hotspot (Gymnopoulos M et al., PMID: 17376864; Keppler-Noreuil KM et al., PMID: 25557259; Madsen R et al., PMID: 30197175). Computational predictors indicate that this 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). 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). Other variants in the same codon, c.1635G>T (p.Glu545Asp), c.1634A>G (p.Glu545Gly), c.1633G>C (p.Glu545Gln), and c.1633G>A (p.Glu545Lys) have been reported in individuals with PROS disorders and cancers and are considered pathogenic/ likely pathogenic (Luks VL et al., PMID: 25681199; McNulty SN et al., PMID: 31585106; Mirzaa G et al., PMID: 27631024; Mojarad BA et al., PMID: 39669231; Mori R et al., PMID: 18262558; Serio VB et al., PMID: 37662840; Vahidnezhad H et al., PMID: 27037860; Wakuda K et al., PMID: 24657128; Wang WF et al., PMID: 24241346; ClinVar Variation IDs: 217293, 13656, 375896, 13655). 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; Parker VER et al., PMID: 30270358; Venot Q et al., PMID: 29899452). Based on an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1634A>C (p.Glu545Ala) variant is classified as pathogenic.

Abnormal cardiovascular system morphology Pathogenic:1

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Ovarian neoplasm Pathogenic:1

Dec 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hepatocellular carcinoma Pathogenic:1

Feb 17, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.77		Loss of ubiquitination at K548 (P = 0.0464)
MVP		0.93
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.86
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121913274; hg19: chr3-178936092; COSMIC: COSV55873209; COSMIC: COSV55873209;