rs2230461

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. BA1PM1_SupportingBS2PP2

This summary comes from the ClinGen Evidence Repository: The c.1173A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Ile391Met). 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). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2113 in African/African American population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). This variant was identified the homozygous state in >3 individuals within control databases (BS2). 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). In summary, this variant meets the criteria to be classified as Benign 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: PM1_P, BA1, BS2, PP2; -10 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA161490/MONDO:0100283/018

Frequency

Genomes: 𝑓 0.10 ( 1192 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3729 hom. )

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9O:2

Conservation

PhyloP100: 1.33

Publications

127 publications found

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 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PIK3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

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

PP2

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

BS2

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

BA1

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.1173A>G	p.Ile391Met	missense_variant	Exon 7 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.1173A>G	p.Ile391Met	missense_variant	Exon 7 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.1173A>G	p.Ile391Met	missense_variant	Exon 7 of 21	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15273

AN:

151982

Hom.:

1188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0769

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0636

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.0621

AC:

15419

AN:

248260

AF XY:

0.0593

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.0528

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0657

Gnomad OTH exome

AF:

0.0826

GnomAD4 exome

AF:

0.0625

AC:

91077

AN:

1457418

Hom.:

3729

Cov.:

AF XY:

0.0611

AC XY:

44326

AN XY:

725112

show subpopulations

African (AFR)

AF:

0.212

AC:

7058

AN:

33336

American (AMR)

AF:

0.0571

AC:

2542

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3392

AN:

26060

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39560

South Asian (SAS)

AF:

0.0197

AC:

1692

AN:

85748

European-Finnish (FIN)

AF:

0.0281

AC:

1499

AN:

53314

Middle Eastern (MID)

AF:

0.139

AC:

799

AN:

5758

European-Non Finnish (NFE)

AF:

0.0626

AC:

69428

AN:

1108910

Other (OTH)

AF:

0.0775

AC:

4664

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3655

7310

10964

14619

18274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2630

5260

7890

10520

13150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.100

AC:

15283

AN:

152100

Hom.:

1192

Cov.:

AF XY:

0.0957

AC XY:

7117

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.211

AC:

8757

AN:

41444

American (AMR)

AF:

0.0769

AC:

1175

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

431

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0143

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0170

AC:

180

AN:

10602

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0636

AC:

4322

AN:

67986

Other (OTH)

AF:

0.106

AC:

223

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

653

1306

1958

2611

3264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0806

Hom.:

1380

Bravo

AF:

0.113

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0519

AC:

200

ESP6500AA

AF:

0.201

AC:

751

ESP6500EA

AF:

0.0680

AC:

558

ExAC

AF:

0.0649

AC:

7839

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0778

EpiControl

AF:

0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 11, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.1173A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Ile391Met). 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). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2113 in African/African American population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). This variant was identified the homozygous state in >3 individuals within control databases (BS2). 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). In summary, this variant meets the criteria to be classified as Benign 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: PM1_P, BA1, BS2, PP2; -10 points (VCEP specifications version 1; Approved: 1/31/2021) -

Cowden syndrome 5

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cowden syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

Benign

0.081

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.76

D;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.24

Sift

Benign

0.15

T;.

Sift4G

Benign

0.10

T;.

Polyphen

0.011

B;.

Vest4

0.096

MPC

0.83

ClinPred

0.0076

GERP RS

-0.00076

Varity_R

0.31

gMVP

0.61

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over