Variant rs121913287 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_006218.4(PIK3CA):c.263G>A(p.Arg88Gln) 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.69

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 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 3-179199088-G-A is Pathogenic according to our data. Variant chr3-179199088-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179199088-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4 linkuse as main transcript	c.263G>A	p.Arg88Gln	missense_variant	2/21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5 linkuse as main transcript	c.263G>A	p.Arg88Gln	missense_variant	2/21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 linkuse as main transcript	c.263G>A	p.Arg88Gln	missense_variant	2/21	2	NM_006218.4	ENSP00000263967	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Megalencephaly-capillary malformation-polymicrogyria syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Cowden syndrome 5 (MIM#615108) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) (MIM#602501). (I) 0107 - This gene is associated with autosomal dominant disease. In addition, MCAP is often associated with post-zygotic mosaicism (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in gnomAD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in MCAP patients, and in most cases, was de novo and confirmed to be a result of post-zygotic mosaicism. It has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 22729224, 29296277, 28941273, 32778138). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 30, 2024	mosaic -

PIK3CA related overgrowth syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

- -

Abnormal cerebral morphology

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2023

Identified in a patient with a clinical diagnosis of megalencephaly-capillary malformation with recurrent ketotic hypoglycemia in published literature (McDermott et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22729224, 28941273) -

Cowden syndrome 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Feb 03, 2023

- -

CLOVES syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Cowden syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2019

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to have conflicting or insufficient data to determine the effect on PIK3CA protein function (PMID: 22949682). This variant has been observed in individuals affected with megalencephaly-capillary malformation syndrome, including (PMID: 22729224, 28941273). In at least one of these individuals, the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 376049). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 88 of the PIK3CA protein (p.Arg88Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

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

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Pathogenic

0.81

Sift

Benign

0.054

T;.;D

Sift4G

Benign

0.063

T;.;D

Polyphen

1.0

D;.;.

Vest4

0.84

MutPred

0.77

Loss of catalytic residue at R88 (P = 0.0883);Loss of catalytic residue at R88 (P = 0.0883);Loss of catalytic residue at R88 (P = 0.0883);

MVP

0.93

MPC

2.0

ClinPred

0.99

GERP RS

5.4

Varity_R

0.74

gMVP

0.86

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