3-179234297-A-T

Position:

chr3-179234297-A-T

Variant summary

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

The NM_006218.4(PIK3CA):c.3140A>T(p.His1047Leu) 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. H1047R) 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:14O:2

Conservation

PhyloP100: 8.85

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 Pathogenic. Variant got 15 ACMG points.

PM1

In a helix (size 15) in uniprot entity PK3CA_HUMAN there are 6 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-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with 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 3-179234297-A-T is Pathogenic according to our data. Variant chr3-179234297-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179234297-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4 linkuse as main transcript	c.3140A>T	p.His1047Leu	missense_variant	21/21	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 linkuse as main transcript	c.3140A>T	p.His1047Leu	missense_variant	21/21		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.3140A>T	p.His1047Leu	missense_variant	21/21	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CLOVES syndrome

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.3140A>T (p.H1047L) alteration is located in exon 21 (coding exon 20) of the PIK3CA gene. This alteration results from an A to T substitution at nucleotide position 3140, causing the histidine (H) at amino acid position 1047 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/248274) total alleles studied. The highest observed frequency was 0.001% (1/112236) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with PIK3CA-related disorders (Lindhurst, 2012; Luks, 2015; Sasaki, 2023). Another alteration at the same codon, c.3140A>G (p.H1047R), has also been detected in multiple individuals with features consistent with PIK3CA-related disorders (Pagliazzi, 2021; Delgado-Miguel, 2021; Rios, 2013; Lindhurst, 2012; Kurek, 2012; Mirzaa, 2016; D'Gama, 2015). 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). In vitro studies demonstrated the variant to have increased growth-promoting activity and exhibit robust activation of the PI3K/AKT/mTOR pathway (Dogruluk, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cavernous lymphangioma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Tissue Medicine and Pathology, University of Bern

Mar 19, 2024

- -

Cowden syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 27, 2021

This variant has previously been reported in numerous unrelated individuals with PIK3CA-related segmental overgrowth syndrome, including individuals with venous malformations (PMID: 25681199, PMID: 27631024, PMID: 28151489, NBK153722). The p.H1047L variant substitutes the histidine with leucine at position 1047 within the PIK3CA kinase domain. This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007). -

Breast adenocarcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

CLAPO syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2012

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 07, 2018

This variant was identified as de novo -

PIK3CA related overgrowth syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Nov 25, 2014

- -

Colorectal cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Apr 02, 2020

- -

Stroke disorder;C0158768:Macrodactyly of toe

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Hemihypertrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

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

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.29

Eigen

Benign

-0.31

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-0.90

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

1.5

REVEL

Uncertain

0.36

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.010

Vest4

0.78

MutPred

0.38

Loss of disorder (P = 0.0418);

MVP

0.94

MPC

1.8

ClinPred

0.30

GERP RS

6.1

Varity_R

0.59

gMVP

0.95

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