rs587776932

chr3-179230077-G-Achr3-179230077-G-Cchr3-179230077-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006218.4(PIK3CA):c.2740G>A(p.Gly914Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 9.49

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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIK3CA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 3-179230077-G-A is Pathogenic according to our data. Variant chr3-179230077-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39703.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-179230077-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.2740G>A	p.Gly914Arg	missense_variant	19/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.2740G>A	p.Gly914Arg	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2740G>A	p.Gly914Arg	missense_variant	19/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Apr 30, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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 -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -

PIK3CA related overgrowth syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Care4Rare-SOLVE, CHEO

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- -

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 12, 2022

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) -

Abnormal cerebral morphology Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

-

- -

Abnormal cardiovascular system morphology Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

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Cowden syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 20, 2020

- -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

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). -

Angioosteohypertrophic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 16, 2019

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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
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	D
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

Other links and lift over

dbSNP: rs587776932; hg19: chr3-178947865; COSMIC: COSV55930478; COSMIC: COSV55930478;