3-179234296-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The NM_006218.4(PIK3CA):c.3139C>T(p.His1047Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1047L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CA
NM_006218.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 7.48

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 15 ACMG points.

PM1

In a domain PI3K/PI4K catalytic (size 286) in uniprot entity PK3CA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_006218.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-179234297-A-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

PP5

Variant 3-179234296-C-T is Pathogenic according to our data. Variant chr3-179234296-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4 link	c.3139C>T	p.His1047Tyr	missense_variant	Exon 21 of 21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.3139C>T	p.His1047Tyr	missense_variant	Exon 21 of 21		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.3139C>T	p.His1047Tyr	missense_variant	Exon 21 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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:3

Mar 08, 2022

Developmental Brain Disorders Lab, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with stron evidence (ClinVar ID: VCV000039705.10, PS1).The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.His1047Leu) has been reported as pathogenic (VCV000013653.15 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.900, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

PIK3CA related overgrowth syndrome

Pathogenic:2

Care4Rare-SOLVE, CHEO

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 11, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PIK3CA c.3139C>T (p.His1047Tyr) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.3139C>T (p.His1047Tyr) variant has been reported in multiple individuals affected with PROS disorders (Parker VER et al., PMID: 30270358; McNulty SN et al., PMID: 31585106; Gökpınar İli E et al., PMID: 35238469; Chen WL et al., PMID: 35483878; Tian W et al., PMID: 33054853). This variant has been reported in the ClinVar database as pathogenic by multiple submitters (ClinVar ID: 39705) and has been reported in multiple cancer cases in the cancer database COSMIC (COSMIC ID: COSV55876499). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the kinase domain, amino acids 765-1051, of PIK3CA, which is defined as a critical functional domain (Zhao L et al., PMID: 18268322). Functional studies show increased phosphorylation and increased transforming ability, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's 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 (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.3139C>T (p.His1047Tyr) variant is classified as pathogenic. -

not provided

Pathogenic:2

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that H1047Y is associated with higher phosphorylation levels of Akt and S6K than wild type, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 17376864); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22729224, 32778138, 32019278, 34322384, 30547809, 33054853, 33057194, 35982159, 37452404, 17376864) -

PIK3CA overgrowth syndrome

Pathogenic:1

Nov 30, 2020

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 histidine with tyrosine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Tyr variant have previously been reported (PMID: 28151489, PMID: 27631024, PMID: 22729224). Further supporting pathogenicity, different missense changes at the same residue (p.His1047Arg, p.His1047Leu, and p.His1047Gln) have been classified as pathogenic (PMID: 25681199, PMID: 28328134 and others). -

Inborn genetic diseases

Pathogenic:1

Jul 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3139C>T (p.H1047Y) alteration is located in exon 21 (coding exon 20) of the PIK3CA gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the histidine (H) at amino acid position 1047 to be replaced by a tyrosine (Y). 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 mutation in two individuals in a megalencephaly-capillary malformation cohort (Rivière, 2012). This variant was also identified as mosaic in other individuals with segmental overgrowth, leg length discrepancy, macrodactyly, vascular malformation, congenital lipomatous truncal overgrowth, and other clinical features consistent with PIK3CA-related disorders (Mirzaa, 2016; Tian, 2020; Chen, 2022). Two other alterations at the same codon, c.3140A>G (p.H1047R) and c.3140A>T (p.H1047L), have been detected in individuals with macrodactyly, congenital progressive segmental overgrowth, lower limb discrepancy, and/or capillaro-lymphatico-venous malformation (Lindhurst, 2012; Sasaki, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Segmental undergrowth associated with mainly venous malformation with capillary component

Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seborrheic keratosis;C0038356:Neoplasm of stomach;C0265552:Congenital macrodactylia;C0334082:Epidermal nevus;C0346153:Familial cancer of breast;C0684249:Lung carcinoma;C0699790:Carcinoma of colon;C0919267:Ovarian neoplasm;C1865285:Megalencephaly-capillary malformation-polymicrogyria syndrome;C2239176:Hepatocellular carcinoma;C2751313:CLAPO syndrome;C2752042:CLOVES syndrome;C3554518:Cowden syndrome 5

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMIFACIAL MYOHYPERPLASIA, SOMATIC

Pathogenic:1

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Non-small cell lung carcinoma

Pathogenic:1

Mar 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed and confirmed as a somatic variant in large intestine, endometrium, breast and ovarian tumors (COSMIC). Somatic PIK3CA variants have been identified in up to 4% of cases of lung cancer (Samuels 2004). -

Cowden syndrome

Pathogenic:1

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1047 of the PIK3CA protein (p.His1047Tyr). 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 (PMID: 22729224, 27631024). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39705). 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. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 17376864). For these reasons, this variant has been classified as Pathogenic. -

CLOVES syndrome

Pathogenic:1

Aug 01, 2021

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Benign

-0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-1.2

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.76

REVEL

Uncertain

0.40

Sift

Benign

0.15

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.90

MutPred

0.42

Gain of phosphorylation at H1047 (P = 0.0483);

MVP

0.97

MPC

1.6

ClinPred

0.94

GERP RS

6.1

Varity_R

0.35

gMVP

0.94

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