NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys) AND Cowden syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 30, 2021
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:: RCV002524695.3

Allele description [Variation Report for NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys)]

NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys)

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.241G>A (p.Glu81Lys)

HGVS:

NC_000003.12:g.179199066G>A
NG_012113.2:g.55544G>A
NM_006218.4:c.241G>AMANE SELECT
NP_006209.2:p.Glu81Lys
LRG_310t1:c.241G>A
LRG_310:g.55544G>A
NC_000003.11:g.178916854G>A
NM_006218.2:c.241G>A
NM_006218.3:c.241G>A

Protein change:

E81K

Links:

dbSNP: rs1057519929

NCBI 1000 Genomes Browser:

rs1057519929

Molecular consequence:

NM_006218.4:c.241G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cowden syndrome (CS)
Synonyms:: Cowden's disease; Cowden's syndrome; Cowden disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0016063; MedGen: C0018553; Orphanet: 201; OMIM: PS158350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003525471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22729224, 25915946, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003525471

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2021)

germline

clinical testing

PubMed (3)
[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	unknown	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

Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors.

Loconte DC, Grossi V, Bozzao C, Forte G, Bagnulo R, Stella A, Lastella P, Cutrone M, Benedicenti F, Susca FC, Patruno M, Varvara D, Germani A, Chessa L, Laforgia N, Tenconi R, Simone C, Resta N.

PLoS One. 2015;10(4):e0123092. doi: 10.1371/journal.pone.0123092.

PubMed [citation]

PMID:: 25915946
PMCID:: PMC4411002

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003525471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 376478). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PMID: 22729224, 25915946). In at least one individual the variant was observed to be de novo. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PIK3CA protein (p.Glu81Lys).

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

Last Updated: Nov 10, 2024

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