rs587776932

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1_SupportingPS4PS2PP2PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2740G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Gly914Arg). This variant is absent from gnomAD v2.1.1 (PM2_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). 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 prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; identified in 5 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), and in 4 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID:22729224), and it was identified in 2 tumor samples in COSMIC (PMID:22729224, PMID:28151489, PMID:28502725, PMID:30231930). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID:22729224). 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, PP2, PM1_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA130467/MONDO:0016054/018

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:22

Conservation

PhyloP100: 9.49

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:

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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.

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.2740G>A	p.Gly914Arg	missense_variant	Exon 19 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.2740G>A	p.Gly914Arg	missense_variant	Exon 19 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.2740G>A	p.Gly914Arg	missense_variant	Exon 19 of 21	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:5

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 19, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Genetics and Personalized Medicine Clinic, Tartu University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory in individuals with overgrowth, macrocephaly, hemihypertrophy, and polydactyly or syndactyly -

not provided

Pathogenic:4

Jul 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22729224, 24939587, 25106414, 23592320, 27631024, 28151489, 28737257, 29346770, 30231930, 32608066, 32595695, 33942430, 33415748, 32778138, 33604570, 34066481, 34097172, 31677919, 33105631, 31729162, 32042194, 33077954, 27535533) -

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PIK3CA related overgrowth syndrome

Pathogenic:3

Care4Rare-SOLVE, CHEO

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a recurrent pathogenic variant that has been described in several individuals with PIK3CA-related overgrowth syndromes (PROS) (PMID: 22729224, PMID: 27631024, PMID: 28151489, PMID: 30231930, and others). The p.Gly914Arg variant substitutes the glycine at codon 914 with arginine within the PI3K/PI4K kinase domain of the PIK3CA protein (UniProt P42336). This variant has not been observed in large population studies (gnomAD v4.1.0). -

Oct 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.2740G>A (p.Gly914Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PROS disorders (Maguolo A et al., PMID: 30231930; Mills JR et al., PMID: 28737257; Park HJ et al., PMID: 32778138; McNulty SN et al., PMID: 31585106) and in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55930478). It has been reported in the ClinVar database as pathogenic/likely pathogenic in both a somatic and a germline state by several submitters including an expert panel (ClinVar Variation ID: 39703) This variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. The PIK3CA c.2740G>A (p.Gly914Arg) 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 et al., PMID: 35997716). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. In support of this prediction, functional studies have shown this variant to cause a significant increase in the phosphorylation levels in a patient cell line (Rivière JB et al., PMID: 22729224). The PIK3CA gene is defined by ClinGen's 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 et al, PMID: 35997716). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.2740G>A (p.Gly914Arg) variant is classified as pathogenic. -

PIK3CA-related disorder

Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PIK3CA c.2740G>A variant is predicted to result in the amino acid substitution p.Gly914Arg. This variant has been identified as de novo (apparently constitutional and mosaic) in multiple individuals with PIK3CA-related overgrowth disorders and polymicrogyria (see for example, Rivière et al. 2012. PubMedID: 22729224, Table 4, Mirzaa. 2016. PubMed ID: 27631024; Table 1, Stutterd. 2021. PubMed ID: 33604570; PreventionGenetics, internal data). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/39703/). This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jul 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2740G>A (p.G914R) alteration is located in exon 19 (coding exon 18) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 2740, causing the glycine (G) at amino acid position 914 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported as a de novo occurrence and heterozygous in multiple individuals with megalencephaly, overgrowth, vascular malformations and/or other clinical features consistent with PIK3CA-related disorders; this variant was detected in multiple sample types for some individuals (Rivière, 2012; Mirzaa, 2016; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cowden syndrome 5

Pathogenic:1

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cowden syndrome

Pathogenic:1

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 39703). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PROS) (PMID: 22729224, 27631024, 30231930, 32595695). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 914 of the PIK3CA protein (p.Gly914Arg). -

CLOVES syndrome

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PS2,PM2 -

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

Pathogenic:1

Feb 12, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2740G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Gly914Arg). This variant is absent from gnomAD v2.1.1 (PM2_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). 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 prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; identified in 5 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), and in 4 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and it was identified in 2 tumor samples in COSMIC (PMID: 22729224, PMID: 28151489, PMID: 28502725, PMID: 30231930). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID: 22729224). 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, PP2, PM1_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021) -

PIK3C1-related disorder

Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_P, PP2, PM1_P, PS4, PS2 -

Abnormal cerebral morphology

Pathogenic:1

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abnormal cardiovascular system morphology

Pathogenic:1

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Angioosteohypertrophic syndrome

Pathogenic:1

Dec 16, 2019

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 glycine at position 941 with arginine within the kinase domain of the PIK3CA protein. This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 22729224, PMID: 27631024, PMID: 28151489, PMID: 30231930). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.8

L;.

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0030

D;.

Polyphen

0.97

D;.

Vest4

0.86

MutPred

0.92

Gain of disorder (P = 0.2761);Gain of disorder (P = 0.2761);

MVP

0.98

MPC

2.5

ClinPred

0.99

GERP RS

5.6

Varity_R

0.91

gMVP

1.0

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