rs2230461

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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:

PIK3CA (HGNC:):

PIK3CA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4 linkuse as main transcript	c.1173A>G	p.Ile391Met	missense_variant	7/21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 linkuse as main transcript	c.1173A>G	p.Ile391Met	missense_variant	7/21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 linkuse as main transcript	c.1173A>G	p.Ile391Met	missense_variant	7/21	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

GnomAD3 exomes

AF:

0.0621

AC:

15419

AN:

248260

Hom.:

792

AF XY:

0.0593

AC XY:

7988

AN XY:

134692

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 SAS exome

AF:

0.0193

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

Gnomad4 AFR exome

AF:

0.212

Gnomad4 AMR exome

AF:

0.0571

Gnomad4 ASJ exome

AF:

0.130

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0197

Gnomad4 FIN exome

AF:

0.0281

Gnomad4 NFE exome

AF:

0.0626

Gnomad4 OTH exome

AF:

0.0775

GnomAD4 genome

AF:

0.100

AC:

15283

AN:

152100

Hom.:

1192

Cov.:

AF XY:

0.0957

AC XY:

7117

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.211

Gnomad4 AMR

AF:

0.0769

Gnomad4 ASJ

AF:

0.124

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.0170

Gnomad4 NFE

AF:

0.0636

Gnomad4 OTH

AF:

0.106

Alfa

AF:

0.0759

Hom.:

789

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

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

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

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 11, 2022

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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Cowden syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

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

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;.

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

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