3-179199066-G-A

Variant names:

• chr3-179199066-G-A
• rs1057519929
• NM_006218.4:c.241G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.241G>A​(p.Glu81Lys) variant causes a missense change. 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 (★★). ClinVar reports functional evidence for this variant: "SCV002525572: Experimental studies have demonstrated that the p.Glu81Lys variant causes overactivation of the PI3K/AKT/mTOR pathway (PMID:25915946).; SCV004176917: Functional in vitro studies show that this variant induces Akt-mTOR signaling and enhanced cell growth, indicating that this variant impacts protein function (Jin N et al., PMID:34779417; Loconte DC et al., PMID:25915946).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 6.36
• Publications: 124 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

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002525572: Experimental studies have demonstrated that the p.Glu81Lys variant causes overactivation of the PI3K/AKT/mTOR pathway (PMID: 25915946).; SCV004176917: Functional in vitro studies show that this variant induces Akt-mTOR signaling and enhanced cell growth, indicating that this variant impacts protein function (Jin N et al., PMID: 34779417; Loconte DC et al., PMID: 25915946).
• PM1: In a domain PI3K-ABD (size 89) in uniprot entity PK3CA_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) 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 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, 0.88
• PP5: Variant 3-179199066-G-A is Pathogenic according to our data. Variant chr3-179199066-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376478.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.241G>A	p.Glu81Lys	missense	Exon 2 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.241G>A	p.Glu81Lys	missense	Exon 2 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.241G>A	p.Glu81Lys	missense	Exon 2 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.241G>A	p.Glu81Lys	missense	Exon 3 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	CLOVES syndrome (1)
1	-	-	Cowden syndrome (1)
1	-	-	Megalencephaly-capillary malformation-polymicrogyria syndrome (1)
1	-	-	PIK3CA related overgrowth syndrome (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.70		Gain of methylation at E81 (P = 0.0034)
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1057519929; hg19: chr3-178916854; COSMIC: COSV55873676; COSMIC: COSV55873676;