rs867262025

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4PS2PP2PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2176G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu726Lys). 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). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in at least 15 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID:28566443), and is in at least 15 tumor samples in the literature and COSMIC (PMID:22729224, PMID:28941273, PMID:24497998 )). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 22729224, 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, PS4_VS, PS2; 14 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602910/MONDO:0016054/018

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.60

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 10 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.

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.2176G>A	p.Glu726Lys	missense_variant	Exon 14 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.2176G>A	p.Glu726Lys	missense_variant	Exon 14 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.2176G>A	p.Glu726Lys	missense_variant	Exon 14 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:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 24, 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 results in a lysine residue replacing a glutamic acid residue at position 726 within the PIK3CA protein. This variant has been previously reported in several unrelated individuals with PIK3CA related overgrowth syndrome (PMID:22729224, PMID:27631024). -

Jun 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34093841, 35238469, 31699932, 24497998, 22729224, 26351730, 28941273, 33644862, 37624421, 36458889) -

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PIK3CA related overgrowth syndrome

Pathogenic:2

Sep 15, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.2176G>A (p.Glu726Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Gökpınar İli E et al., PMID: 35238469; Mirzaa G et al., PMID: 27631024; McNulty SN et al., PMID: 31585106; Leiter SM et al., PMID: 2856644) and in multiple cases in the cancer database COSMIC (Genomic Mutation ID COSV55875460). It has also been classified in the ClinVar database as a germline pathogenic variant by four submitters and as a somatic pathogenic variant by three submitters (ClinVar ID: 376476). The PIK3CA c.2176G>A (p.Glu726Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies using patient-derived cells studies show that this glutamic acid substitution to lysine at codon 726 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Leiter SM et al., PMID: 2856644). The PIK3CA gene is defined by the ClinGen Brain Malformations Variant Curation 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 (Lai A et al., PMID: 35997716). 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.2176G>A (p.Glu726Lys) variant is classified as pathogenic. -

Care4Rare-SOLVE, CHEO

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:2

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000376476). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22729224). Different missense changes at the same codon (p.Glu726Ala, p.Glu726Gly) have been reported to be associated with PIK3CA-related disorder (ClinVar ID: VCV000376477 / PMID: 29549527). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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.2176G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu726Lys). 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). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in at least 15 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 28566443), and is in at least 15 tumor samples in the literature and COSMIC (PMID: 22729224, PMID: 28941273, PMID: 24497998 )). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 22729224, 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, PS4_VS, PS2; 14 points (VCEP specifications version 1; Approved: 1/31/2021) -

Inborn genetic diseases

Pathogenic:1

Feb 20, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2176G>A (p.E726K) alteration is located in exon 14 (coding exon 13) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 2176, causing the glutamic acid (E) at amino acid position 726 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo post-zygotic mutation in multiple individual with features consistent with PIK3CA-related disorders (Rivière, 2012; Tapper, 2014; McDermott, 2016; Mirzaa, 2016; Kuentz, 2017; McDermott, 2017; Ambry internal data). 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). A functional analysis of patient derived cells have shown a significant increase of phosphorylation levels for p.E726K (Leiter, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cowden syndrome

Pathogenic:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 726 of the PIK3CA protein (p.Glu726Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome and/or PIK3CA-related conditions (PMID: 22729224, 24497998, 26351730, 27631024; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376476). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.64

N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.25

N;.

REVEL

Uncertain

0.44

Sift

Benign

0.81

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.87

P;.

Vest4

0.74

MutPred

0.34

Gain of MoRF binding (P = 0.0033);Gain of MoRF binding (P = 0.0033);

MVP

0.95

MPC

2.1

ClinPred

0.65

GERP RS

5.7

Varity_R

0.50

gMVP

0.56

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