NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys) AND PIK3CA related overgrowth syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002472374.8

Allele description [Variation Report for NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)]

NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)

Gene:

PIK3CA:phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q26.32

Genomic location:

Preferred name:

NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)

HGVS:

NC_000003.12:g.179210291G>A
NG_012113.2:g.66769G>A
NM_006218.4:c.1357G>AMANE SELECT
NP_006209.2:p.Glu453Lys
LRG_310t1:c.1357G>A
LRG_310:g.66769G>A
NC_000003.11:g.178928079G>A
NM_006218.2:c.1357G>A
NM_006218.3:c.1357G>A
p.E453K

Protein change:

E453K

Links:

dbSNP: rs1057519925

NCBI 1000 Genomes Browser:

rs1057519925

Molecular consequence:

NM_006218.4:c.1357G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PIK3CA related overgrowth syndrome
Synonyms:: PIK3CA related overgrowth spectrum; PIK3CA-associated segmental overgrowth; PIK3CA-Related Segmental Overgrowth
Identifiers:: MONDO: MONDO:1040002; MedGen: C4728213

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557944	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22729224, 27631024, 30063105, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557944

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.

Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, et al.

Nat Genet. 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331.

PubMed [citation]

PMID:: 22729224
PMCID:: PMC3408813

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mirzaa G, Timms AE, Conti V, Boyle EA, Girisha KM, Martin B, Kircher M, Olds C, Juusola J, Collins S, Park K, Carter M, Glass I, Krägeloh-Mann I, Chitayat D, Parikh AS, Bradshaw R, Torti E, Braddock S, Burke L, Ghedia S, Stephan M, et al.

JCI Insight. 2016 Jun 16;1(9). doi:pii: 87623. 10.1172/jci.insight.87623.

PubMed [citation]

PMID:: 27631024
PMCID:: PMC5019182

See all PubMed Citations (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557944.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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