rs121913272

Positions:

• chr3-179210192-T-C
• chr3-179210192-T-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1258T>C​(p.Cys420Arg) 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. C420G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a strand (size 10) in uniprot entity PK3CA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr3-179210192-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376469.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 3-179210192-T-C is Pathogenic according to our data. Variant chr3-179210192-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 31945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179210192-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1258T>C	p.Cys420Arg	missense_variant	8/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1258T>C	p.Cys420Arg	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1258T>C	p.Cys420Arg	missense_variant	8/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CLAPO syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS1, PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Feb 01, 2022	- -

CLOVES syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Feb 23, 2021	This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome, including isolated lymphatic malformation (PMID: 25681199). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). The p.Cys420Arg replaces the cysteine at codon 420 with arginine within the C2 domain of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Cys240Arg variant causes overactivation of the PI3K/AKT/mTOR pathway and increased proliferation in vitro (PMID: 26627007). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PIK3CA: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP4, PS3:Supporting -

Ovarian neoplasm Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 08, 2010	- -
Likely pathogenic, no assertion criteria provided	research	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 01, 2018	- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Segmental undergrowth associated with lymphatic malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Apr 06, 2021

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Capillary malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 420 of the PIK3CA protein (p.Cys420Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PIK3CA-related overgrowth syndrome (PMID: 22658544, 24782230; Invitae). ClinVar contains an entry for this variant (Variation ID: 31945). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 15930273, 17376864, 18074223, 22120714, 22949682). For these reasons, this variant has been classified as Pathogenic. -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Apr 23, 2014

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Rare combined vascular malformation Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Adenoid cystic carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.79
Sift	Benign	0.035	D;.
Sift4G	Benign	0.32	T;.
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.73		Gain of disorder (P = 0.0054);Gain of disorder (P = 0.0054);
MVP		0.90
MPC		2.3
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.96

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: rs121913272; hg19: chr3-178927980; COSMIC: COSV55874020;