NM_006218.4:c.1633G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1 PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001772130: 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" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E545Q) has been classified as Uncertain significance. The gene PIK3CA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:11
• Conservation: PhyloP100: 9.60
• Publications: 3208 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: 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

ACMG classification

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

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_006218.4 (PIK3CA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001772130: 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); SCV001478679: 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).; SCV004176947: "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)."; SCV002028353: The 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).; SCV002525703: "This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007)."
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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. 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 vascular malformation, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden syndrome 5, megalencephaly-capillary malformation-polymicrogyria syndrome, familial ovarian cancer, hereditary breast carcinoma, Cowden disease.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 13655.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.1633G>A	p.Glu545Lys	missense	Exon 10 of 21	NP_006209.2	P42336

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.1633G>A	p.Glu545Lys	missense	Exon 10 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.1663G>A	p.Glu555Lys	missense	Exon 10 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.1633G>A	p.Glu545Lys	missense	Exon 11 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247990 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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000655 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	CLOVES syndrome (2)
2	-	-	Non-small cell lung carcinoma (2)
2	-	-	not provided (2)
2	-	-	PIK3CA related overgrowth syndrome (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	Angioosteohypertrophic syndrome (1)
1	-	-	Breast adenocarcinoma (1)
1	-	-	Carcinoma of colon (1)
1	-	-	Cerebrofacial Vascular Metameric Syndrome (CVMS) (1)
1	-	-	Eccrine angiomatous hamartoma (1)
1	-	-	Gallbladder cancer (1)
1	-	-	Gastric cancer (1)
1	-	-	HEMIFACIAL MYOHYPERPLASIA, SOMATIC (1)
1	-	-	Megalencephaly-capillary malformation-polymicrogyria syndrome (2)
1	-	-	OVARIAN CANCER, EPITHELIAL, SOMATIC (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
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)
MVP		0.93
MPC		2.8
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.87
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

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