3-179210291-G-A

Position:

• chr3-179210291-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1357G>A​(p.Glu453Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.57

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 3-179210291-G-A is Pathogenic according to our data. Variant chr3-179210291-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179210291-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1357G>A	p.Glu453Lys	missense_variant	8/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1357G>A	p.Glu453Lys	missense_variant	8/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1357G>A	p.Glu453Lys	missense_variant	8/21	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 25, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 06, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Aug 26, 2021	This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2022	Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528) -

CLOVES syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jun 01, 2023	This variant has been identified by standard clinical testing. somatic mutation -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 02, 2022

A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

PIK3CA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Daryl Scott Lab, Baylor College of Medicine

Feb 01, 2022

- -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2021

This sequence change replaces glutamic acid with lysine at codon 453 of the PIK3CA protein (p.Glu453Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with PIK3CA-associated overgrowth conditions (PMID: 27631024, 27631024, 28151489, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376470). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.54
Sift	Benign	0.12	T;.
Sift4G	Benign	0.18	T;.
Polyphen		0.94	P;.
Vest4		0.94
MutPred		0.84		Gain of methylation at E453 (P = 0.021);Gain of methylation at E453 (P = 0.021);
MVP		0.88
MPC		1.7
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.89

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: rs1057519925; hg19: chr3-178928079; COSMIC: COSV55874585;