chr3-179234297-A-G

Position:

• chr3-179234297-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 PM2_Supporting PS3_Moderate PM1_Supporting PS4 PS2_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
• Clinical Significance: Pathogenic reviewed by expert panel P:65 O:2
• Conservation: PhyloP100: 8.85

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 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/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.3140A>G	p.His1047Arg	missense_variant	21/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.3140A>G	p.His1047Arg	missense_variant	21/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.3140A>G	p.His1047Arg	missense_variant	21/21	2	NM_006218.4	ENSP00000263967	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248274 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134662

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.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:65 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PIK3CA: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 05, 2021	PS4, PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Sep 20, 2020	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). -

CLOVES syndrome Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 11, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Jun 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
not provided, no classification provided	literature only	GeneReviews	-	- -

Non-small cell lung carcinoma Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2010	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Ovarian neoplasm Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2010	- -
Pathogenic, no assertion criteria provided	research	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Hepatocellular carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 31, 2016	- -

PIK3CA related overgrowth syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Biesecker Lab Rare Disease, National Institutes of Health	Apr 19, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Apr 01, 2015	- -

Neoplasm Pathogenic:1 Other:1

-, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Jul 14, 2015	- -

Segmental undergrowth associated with mainly venous malformation with capillary component 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

- -

Breast neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Rare venous malformation Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

OVARIAN CANCER, EPITHELIAL, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Feb 12, 2021

- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 11, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

Neoplasm of the large intestine Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

PIK3CA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Apr 06, 2021

- -

CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Papillary renal cell carcinoma type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Medulloblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

CLAPO syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

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

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

-

- -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Rosette-forming glioneuronal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

-

- -

Cerebrofacial Vascular Metameric Syndrome (CVMS) Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

James Bennett Lab, Seattle Childrens Research Institute

Sep 30, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Oncology, Institut Jules Bordet

-

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Seborrheic keratosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Klippel-Trenaunay-like-Syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Mar 23, 2023

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

MACRODACTYLY, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.60	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.019	D
Sift4G	Benign	0.14	T
Polyphen		0.64	P
Vest4		0.72
MutPred		0.63		Gain of MoRF binding (P = 0.0089);
MVP		0.97
MPC		2.4
ClinPred		0.41	T
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

Other links and lift over

dbSNP: rs121913279; hg19: chr3-178952085; COSMIC: COSV55873195; COSMIC: COSV55873195;