rs587776933

Variant names:

• chr3-179210289-TAGA-T
• rs587776933
• NM_006218.4:c.1359_1361delAGA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.1359_1361delAGA​(p.Glu453del) variant causes a disruptive inframe deletion 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 disruptive_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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a domain C2 PI3K-type (size 157) in uniprot entity PK3CA_HUMAN there are 31 pathogenic changes around while only 2 benign (94%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1359_1361delAGA	p.Glu453del	disruptive_inframe_deletion	Exon 8 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1359_1361delAGA	p.Glu453del	disruptive_inframe_deletion	Exon 8 of 21		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1359_1361delAGA	p.Glu453del	disruptive_inframe_deletion	Exon 8 of 21	2	NM_006218.4	ENSP00000263967.3

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

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 22729224); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid(s) 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, 27631024, 27191687, 22729224, 33057194, 35982159) -

Apr 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:2

Jun 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 06, 2021

Medical Genetics Laboratory, Aldo Moro University of Bari

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cowden syndrome Pathogenic:1

Nov 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=40/60	disease causing (ClinVar)

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; COSMIC: COSV55895926;