NM_006218.4(PIK3CA):c.3062A>G (p.Tyr1021Cys) AND Cowden syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 4, 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:: RCV001851016.3

Allele description [Variation Report for NM_006218.4(PIK3CA):c.3062A>G (p.Tyr1021Cys)]

NM_006218.4(PIK3CA):c.3062A>G (p.Tyr1021Cys)

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.3062A>G (p.Tyr1021Cys)

HGVS:

NC_000003.12:g.179234219A>G
NG_012113.2:g.90697A>G
NM_006218.4:c.3062A>GMANE SELECT
NP_006209.2:p.Tyr1021Cys
LRG_310:g.90697A>G
NC_000003.11:g.178952007A>G
NM_006218.3:c.3062A>G

Protein change:

Y1021C

Links:

dbSNP: rs121913288

NCBI 1000 Genomes Browser:

rs121913288

Molecular consequence:

NM_006218.4:c.3062A>G - 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
SCV002129104	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27631024, 22729224, 28151489, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002129104

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 4, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002129104.3

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1021 of the PIK3CA protein (p.Tyr1021Cys). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr1021 amino acid residue in PIK3CA. Other variant(s) that disrupt this residue have been observed in individuals with PIK3CA-related conditions (PMID: 27631024, 28151489; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 376246). This missense change has been observed in individuals with a spectrum of overgrowth conditions (PMID: 22729224, 28151489; Invitae). This variant is not present in population databases (gnomAD no frequency).

#	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: Apr 6, 2024

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