NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 14, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001775789.12

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002013346	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 14, 2022)	germline	clinical testing	Citation Link,
SCV002525708	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2021)	somatic	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002013346

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 14, 2022)

germline

clinical testing

Citation Link,

SCV002525708

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 26, 2021)

somatic

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	somatic	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV002013346.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528)

#	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

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002525708.1

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

Description

This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases)

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

Last Updated: May 19, 2024

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