VCV000039704.13 - ClinVar

NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)

Variation ID: 39704 Accession: VCV000039704.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179204576 (GRCh38) [ NCBI UCSC ] 3: 178922364 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 22, 2015	Mar 10, 2024	Aug 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1133G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Cys378Tyr	missense
NM_006218.3:c.1133G>A
NC_000003.12:g.179204576G>A
NC_000003.11:g.178922364G>A
NG_012113.2:g.61054G>A
LRG_310:g.61054G>A
LRG_310t1:c.1133G>A
	P42336:p.Cys378Tyr

... more HGVS ... less HGVS

Protein change

C378Y

Other names

Canonical SPDI

NC_000003.12:179204575:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA130469 UniProtKB: P42336#VAR_069254 OMIM: 171834.0012 dbSNP: rs397514565 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIK3CA		No evidence available	No evidence available	GRCh38 GRCh37	1303	1337

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Megalencephaly-capillary malformation-polymicrogyria syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV000032908.11
PIK3CA related overgrowth syndrome	Pathogenic (2)	criteria provided, single submitter	-	RCV000201233.2
Cowden syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 30, 2023	RCV000806643.6
PIK3CA-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 30, 2022	RCV004532477.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cowden syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000946653.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22729224‚ 27631024‚ 28151489 Comment: 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, … (more) 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 39704). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (MCAP) and symptoms consistent with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28151489). 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 sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the PIK3CA protein (p.Cys378Tyr). (less)
Pathogenic (Aug 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PIK3CA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004118723.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple … (more) The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. (less)
Pathogenic (Dec 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Megalencephaly-capillary malformation-polymicrogyria syndrome Affected status: yes Allele origin: somatic	Centogene AG - the Rare Disease Company Accession: SCV002059600.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Megalencephaly-capillary malformation-polymicrogyria syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV003842078.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (3) PubMed: 27631024‚ 24459181‚ 26637981 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 26637981). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039704). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). A different missense change at the same codon (p.Cys378Arg) has been reported to be associated with PIK3CA related disorder (ClinVar ID: VCV000917489). The variant was detected at ~13% allele frequency, suggesting mosaic state. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Intellectual disability (present) , Overgrowth (present) , Macrocephaly (present) , Prominent forehead (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Broad … (more) Intellectual disability (present) , Overgrowth (present) , Macrocephaly (present) , Prominent forehead (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Broad fingertip (present) , Prominent fingertip pads (present) , Chiari type I malformation (present) , Thick lower lip vermilion (present) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	PIK3CA related overgrowth syndrome Affected status: yes Allele origin: de novo	Care4Rare-SOLVE, CHEO Accession: SCV003932121.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Number of individuals with the variant: 2
Pathogenic (Jun 24, 2012)	no assertion criteria provided Method: literature only	MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000056680.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 22729224 Comment on evidence: Riviere et al. (2012) performed standard variant calling in exomes from 7 individuals with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and identified a 1133G-A transition in … (more) Riviere et al. (2012) performed standard variant calling in exomes from 7 individuals with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and identified a 1133G-A transition in the PIK3CA gene, resulting in a cys378-to-tyr (C378Y) substitution. The mutation was supported by 68 of 250 reads (27%) in 1 individual. This mutation showed variable levels of mosaicism depending on the tissue tested. (less)
Pathogenic (Dec 08, 2014)	no assertion criteria provided Method: clinical testing	PIK3CA Related Overgrowth Spectrum Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV000255988.2 First in ClinVar: Oct 22, 2015 Last updated: Oct 07, 2023	Indication for testing: Polymicrogyria; Macrocepahly Tissue: Buccal swab

Comment:

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 39704). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (MCAP) and symptoms consistent with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28151489). 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 sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the PIK3CA protein (p.Cys378Tyr).

Comment:

The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 26637981). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039704). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). A different missense change at the same codon (p.Cys378Arg) has been reported to be associated with PIK3CA related disorder (ClinVar ID: VCV000917489). The variant was detected at ~13% allele frequency, suggesting mosaic state. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.	Kuentz P	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28151489
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.	Mirzaa G	JCI insight	2016	PMID: 27631024
Somatic Activating PIK3CA Mutations Cause Venous Malformation.	Limaye N	American journal of human genetics	2015	PMID: 26637981
The structural basis of PI3K cancer mutations: from mechanism to therapy.	Liu S	Cancer research	2014	PMID: 24459181
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.	Rivière JB	Nature genetics	2012	PMID: 22729224

Text-mined citations for rs397514565 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514565 ...