rs587776933

chr3-179210289-TAGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_006218.4(PIK3CA):c.1359_1361del(p.Glu453del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L452L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.57

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 11 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, 5 uncertain in NM_006218.4
• PM4: Nonframeshift variant in NON repetitive region in NM_006218.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-179210289-TAGA-T is Pathogenic according to our data. Variant chr3-179210289-TAGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 39706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1359_1361del	p.Glu453del	inframe_deletion	8/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1359_1361del	p.Glu453del	inframe_deletion	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1359_1361del	p.Glu453del	inframe_deletion	8/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2022	The PIK3CA c.1359_1361del; p.Glu453del variant (rs587776933) is reported in the literature in several individuals affected with megalencephaly-capillary malformation (MCAP) or megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes and was found to occur de novo in at least two (Mirzaa 2016, Riviere 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single glutamate residue leaving the rest of the protein in-frame. Functional studies suggest cells expressing the variant protein have increased phosphatidylinositol-3,4,5-triphosphate levels, suggestive of elevated PI3K-AKT-mTOR signaling (Riviere 2012). Additionally, another variant at this codon (c.1357G>A; p.Glu453Lys) has been reported in individuals with MCAP or other overgrowth syndromes and is considered disease-causing (Mirzaa 2016). Based on available information, the p.Glu453del variant is considered to be pathogenic. References: Mirzaa G et al. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight. 2016 Jun 16;1(9):e87623. PMID: 27631024. Riviere JB et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 Jun 24;44(8):934-40. PMID: 22729224. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	Published functional studies demonstrate a damaging effect. Immunostaining of c.1359_1361delAGA mutant lymphoblastiod cell lines support that this variant impairs protein function, as predicted by in-silico analyses, including protein predictors and evolutionary conservation (Rivire et al., 2012).; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26226847, 26593112, 22729224, 27631024, 27191687) -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Laboratory, Aldo Moro University of Bari	Jun 06, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2022

This variant, c.1359_1361del, results in the deletion of 1 amino acid(s) of the PIK3CA protein (p.Glu453del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39706). This variant has been observed in individual(s) with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28502725, 32778138; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587776933; hg19: chr3-178928077;