3-179234297-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1_SupportingPS4PS2_ModeratePP2PM2_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, 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 (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID:25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123326/MONDO:0016054/018

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:42O:2

Conservation

PhyloP100: 8.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4 link	c.3140A>G	p.His1047Arg	missense_variant	Exon 21 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.3140A>G	p.His1047Arg	missense_variant	Exon 21 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.3140A>G	p.His1047Arg	missense_variant	Exon 21 of 21	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134662

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:42Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CLOVES syndrome

Pathogenic:6Other:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM5+PP2+PM1_Supporting+PS4+PS3_Supporting -

Nov 11, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jun 02, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:6

Aug 05, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3, PM2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a somatic variant in various tumor samples (Campbell et al., 2004; Li et al., 2005); Published functional studies demonstrate increased lipid kinase activity and transforming activities, and a mouse model with this variant demonstrated increased body weight, increased organ size, and severe metabolic defects (Ikenoue et al., 2005; Kinross et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322209, 15289301, 15016963, 25599672, 23100325, 25550458, 15930273, 16432179, 19805105, 21708979, 15520168, 15784156, 27631024, 24903541, 22658544, 32770747, 34568242, 34075207) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIK3CA: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2 -

Sep 20, 2020

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant substitutes the histidine with arginine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Arg variant have previously been reported (PMID: 25681199, PMID: 26637981, PMID: 24903541, PMID: 30180809, PMID: 28328134 and others). -

Ovarian neoplasm

Pathogenic:2

Dec 01, 2018

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 05, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Non-small cell lung carcinoma

Pathogenic:2

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 05, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PIK3CA related overgrowth syndrome

Pathogenic:2

Apr 19, 2019

Biesecker Lab Rare Disease, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2015

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Segmental undergrowth associated with mainly venous malformation with capillary component

Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare venous malformation

Pathogenic:1

Mar 19, 2024

Institute of Tissue Medicine and Pathology, University of Bern

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

OVARIAN CANCER, EPITHELIAL, SOMATIC

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rosette-forming glioneuronal tumor

Pathogenic:1

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebrofacial Vascular Metameric Syndrome (CVMS)

Pathogenic:1

Sep 30, 2021

James Bennett Lab, Seattle Childrens Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast carcinoma

Pathogenic:1

Medical Oncology, Institut Jules Bordet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:1

Feb 12, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Pathogenic:1

Feb 11, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, 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 (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021) -

Congenital macrodactylia

Pathogenic:1

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hepatocellular carcinoma

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Seborrheic keratosis

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PIK3CA-related disorder

Pathogenic:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PIK3CA c.3140A>G variant is predicted to result in the amino acid substitution p.His1047Arg. This variant has been reported to be mosaic in several individuals with CLOVES syndrome or megalencephaly-capillary malformation syndrome (Kurek et al. 2012. PubMed ID: 22658544; D'Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Segmental undergrowth associated with lymphatic malformation

Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Breast adenocarcinoma

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

CLAPO syndrome

Pathogenic:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2, PM5, PP2, PP3, PP4, PP5 -

Lip and oral cavity carcinoma

Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

PIK3CA-Related Overgrowth Spectrum Disorders

Pathogenic:1

May 08, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.3140A>G (p.His1047Arg) variant was identified. This variant has been reported in numerous individuals affected with PROS disorders (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; Mirzaa G et al., PMID: 27631024; Kurek KC et al, PMID: 22658544). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic both in a germline and a somatic state by numerous submitters, including an expert panel (ClinVar ID: 13652). It has also been reported in multiple cases in the cancer database COSMIC (COSMIC ID: COSV55873195). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.3140A>G (p.His1047Arg) variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai A et al., PMID: 35997716). Functional studies showed autonomous activation and enhanced Akt-mTOR signaling in vitro and tumorigenesis in vivo, indicating that this variant impacts protein function (Yuan W et al., PMID: 22370636; Loconte DC et al., PMID: 25915946; Rios JJ et al., PMID: 23100325; Lindhurst MJ et al., PMID: 22729222; Tikoo A et al., PMID: 22666336). Other variants in the same codon, c.3140A>T (p.His1047Leu) and c.3139C>T (p.His1047Tyr), have been reported in individuals with PROS disorders and are considered pathogenic (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; ClinVar ID: 13653, 39705). The PIK3CA gene is defined by the ClinGen Brain Malformation Expert Panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai A et al., PMID: 35997716). 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; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.3140A>G (p.His1047Arg) variant is classified as pathogenic. -

Carcinoma of colon

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Klippel-Trenaunay-like-Syndrome

Pathogenic:1

Mar 23, 2023

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MACRODACTYLY, SOMATIC

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Abnormal cardiovascular system morphology

Pathogenic:1

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Rare combined vascular malformation

Pathogenic:1

Mar 19, 2024

Institute of Tissue Medicine and Pathology, University of Bern

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.60

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.46

Sift

Uncertain

0.019

Sift4G

Benign

0.14

Polyphen

0.64

Vest4

0.72

MutPred

0.63

Gain of MoRF binding (P = 0.0089);

MVP

0.97

MPC

2.4

ClinPred

0.41

GERP RS

6.1

Varity_R

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over